Performance on complex memory tests is associated with ß-amyloid in individuals at risk of developing Alzheimer's disease.

The pathophysiological development of Alzheimer's disease (AD) begins in the brain years before the onset of clinical symptoms. The accumulation of beta-amyloid (Aß) is thought to be the first cortical pathology to occur. Carrying one apolipoprotein E (APOE) ε4 allele increases the risk of developing AD at least 2-3 times and is associated with earlier Aß accumulation. Although it is difficult to identify Aß-related cognitive impairment in early AD with standard cognitive tests, more sensitive memory tests may be able to do this. We sought to examine associations between Aß and performance on three tests within three subdomains of memory, verbal, visual, and associative memory, to elucidate which of these tests were sensitive to Aß-related cognitive impairment in at-risk subjects. 55 APOE ε4 carriers underwent MRI, 11 C-Pittsburgh Compound B (PiB) PET, and cognitive testing. A composite cortical PiB SUVR cut-off score of 1.5 was used to categorise subjects as either APOE ε4 Aß+ or APOE ε4 Aß-. Correlations were carried out using cortical surface analysis. In the whole APOE ε4 group, we found significant correlations between Aß load and performance on verbal, visual, and associative memory tests in widespread cortical areas, the strongest association being with performance on associative memory tests. In the APOE ε4 Aß+ group, we found significant correlations between Aß load and performance of verbal and associative, but not visual, memory in localised cortical areas. Performance on verbal and associative memory tests provides sensitive markers of early Aß-related cognitive impairment in at-risk subjects.

Sertraline treatment influences [18F]FE-PE2I PET imaging for Parkinsonism.

BACKGROUND: The dopamine transporter (DaT) PET ligand [18F]FE-PE2I is used to aid the diagnosis of Parkinson's disease. After encountering four patients with a history of daily sertraline use, who all showed atypical findings on [18F]FE-PE2I PET, we suspected that the selective serotonin reuptake inhibitor (SSRI), sertraline, might interfere with the results and lead to globally reduced striatal [18F]FE-PE2I binding due to sertraline's high affinity for DaT. METHODS: We rescanned the four patients with [18F]FE-PE2I PET after a 5-day sertraline pause. Sertraline plasma concentration was estimated based on body weight and dose, and specific binding ratios (SBR) in caudate nucleus, known to be more preserved in Parkinson's, were used to estimate the effect on tracer binding. Comparison was made to a patient with [18F]FE-PE2I PET before and after a 7-day Modafinil pause. RESULTS: We found a significant effect of sertraline on caudate nucleus SBR (p = 0.029). The effect showed a linear dose-dependent relationship that corresponds to a reduction in SBR by 0.32 or 0.44 for a 75 kg male or a 65 kg female, respectively, taking a daily dose of 50 mg sertraline. CONCLUSION: Sertraline is one of the most commonly used antidepressants and in contrast to other SSRI's, sertraline show high affinity for DaT. We recommend that sertraline treatment is taken into account when patients are undergoing [18F]FE-PE2I PET especially in patients showing apparent globally reduced PE2I binding. If tolerable, pausing of the sertraline treatment should be considered, especially for doses above 50 mg/day.

Correlation Between Cerebral Tissue Oxygen Saturation and Oxygen Extraction Fraction During Anesthesia: Monitoring Cerebral Metabolic Demand-supply Balance During Vasopressor Administration.

BACKGROUND: The speculation that cerebral tissue oxygen saturation (SctO 2 ) measured using tissue near-infrared spectroscopy reflects the balance between cerebral metabolic rate of oxygen and cerebral oxygen delivery has not been validated. Our objective was to correlate SctO 2 with cerebral oxygen extraction fraction (OEF) measured using positron emission tomography; OEF is the ratio between cerebral metabolic rate of oxygen and cerebral oxygen delivery and reflects the balance between these 2 variables. MATERIALS AND METHODS: This cohort study was based on data collected in a previously published trial assessing phenylephrine versus ephedrine treatment in anesthetized patients undergoing brain tumor surgery. The variables of interest were measured twice over the healthy hemisphere before surgery: the first measurement performed after anesthesia induction and the second measurement performed after induction of a ∼20% increase in blood pressure using either phenylephrine or ephedrine. RESULTS: Data from 24 patients were analyzed. The overall vasopressor-induced relative changes in SctO 2 (ΔSctO 2 ) and OEF (ΔOEF) were 3.16% [interquartile range, -0.73% to 6.04%] and -12.5% [interquartile range, -24.0% to -6.19%], respectively. ΔSctO 2 negatively correlated with ΔOEF after phenylephrine treatment (Spearman rank correlation coefficient [ rs ]=-0.76; P =0.007), ephedrine treatment ( rs =-0.76; P =0.006), and any treatment ( rs =-0.79; P <0.001). ΔSctO 2 significantly associated with ΔOEF based on multivariable analysis with ΔOEF, relative changes in mean arterial pressure, arterial blood oxygen tension, and the bispectral index as covariates ( P =0.036). CONCLUSIONS: The negative correlation between changes in SctO 2 and OEF suggests that SctO 2 may reflect the cerebral metabolic demand-supply balance during vasopressor treatment. The generalizability of our findings in other clinical scenarios remains to be determined.

Asymmetric amyloid deposition in preclinical Alzheimer's disease: A PET study.

Introduction: The typical spatial pattern of amyloid-ß (Aß) in diagnosed Alzheimer's disease (AD) is that of a symmetrical hemispheric distribution. However, Aß may be asymmetrically distributed in early stages of AD. Aß distribution on PET has previously been explored in MCI and AD, but it has yet to be directly investigated in preclinical AD (pAD). We examined how Aß was distributed in individuals with pAD and MCI using 11C-Pittsburgh Compound B (PiB) PET. Methods: In this PET study, 79 subjects were retrospectively enrolled, including 34 controls, 24 pAD, and 21 MCI. All subjects underwent APOE genotyping, 11C-PiB PET, MRI, and cognitive testing. We explored differences in Aß load, Aß lateralisation, and Aß distribution, as well as associations between Aß distribution and cognition. Results: The Aß asymmetry index (AI) differed between groups, with pAD having the highest Aß AI as compared to both controls and MCI. There was no clear Aß lateralisation in pAD, but there was a non-significant trend towards Aß being more left-lateralised in MCI. There were no correlations between the cognitive scores and Aß AI or Aß lateralisation in pAD or MCI. Conclusion: The distribution of Aß is most asymmetrical in pAD, as Aß first starts accumulating, and it then becomes less asymmetrical in MCI, when Aß has spread further, suggesting that more pronounced asymmetrical Aß distribution may be a distinguishing factor in pAD. Longitudinal studies examining the distribution of Aß across the AD continuum are needed.

Regional and interindividual relationships between cerebral perfusion and oxygen metabolism.

Quantitative measurements of resting cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) show large between-subject and regional variability, but the relationships between CBF and CMRO2 measurements regionally and globally are not fully established. Here, we investigated the between-subject and regional associations between CBF and CMRO2 measures with independent and quantitative PET techniques. We included resting CBF and CMRO2 measurements from 50 healthy volunteers (aged 22-81 yr), and calculated the regional and global values of oxygen delivery (Do2) and oxygen extraction fraction (OEF). Linear mixed-model analysis showed that CBF and CMRO2 measurements were closely associated regionally, but no significant between-subject association could be demonstrated, even when adjusting for arterial Pco2 and hemoglobin concentration. The analysis also showed regional differences of OEF, reflecting variable relationship between Do2 and CMRO2, resulting in lower estimates of OEF in thalami, brainstem, and mesial temporal cortices and higher estimates of OEF in occipital cortex. In the present study, we demonstrated no between-subject association of quantitative measurements of CBF and CMRO2 in healthy subjects. Thus, quantitative measurements of CBF did not reflect the underlying between-subject variability of oxygen metabolism measures, mainly because of large interindividual OEF variability not accounted for by Pco2 and hemoglobin concentration.NEW & NOTEWORTHY Using quantitative PET-measurements in healthy human subjects, we confirmed a regional association of CBF and CMRO2, but did not find an association of these values across subjects. This suggests that subjects have an individual coupling between perfusion and metabolism and shows that absolute perfusion measurements does not serve as a surrogate measure of individual measures of oxygen metabolism. The analysis further showed smaller, but significant regional differences of oxygen extraction fraction at rest.

Ephedrine versus Phenylephrine Effect on Cerebral Blood Flow and Oxygen Consumption in Anesthetized Brain Tumor Patients: A Randomized Clinical Trial.

BACKGROUND: Studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation compared with ephedrine. The present study aimed to quantify the effects of phenylephrine and ephedrine on cerebral blood flow and cerebral metabolic rate of oxygen in brain tumor patients. The authors hypothesized that phenylephrine reduces cerebral metabolic rate of oxygen in selected brain regions compared with ephedrine. METHODS: In this double-blinded, randomized clinical trial, 24 anesthetized patients with brain tumors were randomly assigned to ephedrine or phenylephrine treatment. Positron emission tomography measurements of cerebral blood flow and cerebral metabolic rate of oxygen in peritumoral and normal contralateral regions were performed before and during vasopressor infusion. The primary endpoint was between-group difference in cerebral metabolic rate of oxygen. Secondary endpoints included changes in cerebral blood flow, oxygen extraction fraction, and regional cerebral oxygen saturation. RESULTS: Peritumoral mean ± SD cerebral metabolic rate of oxygen values before and after vasopressor (ephedrine, 67.0 ± 11.3 and 67.8 ± 25.7 µmol · 100 g · min; phenylephrine, 68.2 ± 15.2 and 67.6 ± 18.0 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 1.5 [-13.3 to 16.3] µmol · 100 g · min [P = 0.839]). Corresponding contralateral hemisphere cerebral metabolic rate of oxygen values (ephedrine, 90.8 ± 15.9 and 94.6 ± 16.9 µmol · 100 g · min; phenylephrine, 100.8 ± 20.7 and 96.4 ± 17.7 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 8.2 [-2.0 to 18.5] µmol · 100 g · min [P = 0.118]). Ephedrine significantly increased cerebral blood flow (difference [95% CI], 3.9 [0.7 to 7.0] ml · 100 g · min [P = 0.019]) and regional cerebral oxygen saturation (difference [95% CI], 4 [1 to 8]% [P = 0.024]) in the contralateral hemisphere compared to phenylephrine. The change in oxygen extraction fraction in both regions (peritumoral difference [95% CI], -0.6 [-14.7 to 13.6]% [P = 0.934]; contralateral hemisphere difference [95% CI], -0.1 [- 12.1 to 12.0]% [P = 0.989]) were comparable between groups. CONCLUSIONS: The cerebral metabolic rate of oxygen changes in peritumoral and normal contralateral regions were similar between ephedrine- and phenylephrine-treated patients. In the normal contralateral region, ephedrine was associated with an increase in cerebral blood flow and regional cerebral oxygen saturation compared with phenylephrine.

Quantitative and clinical impact of MRI-based attenuation correction methods in [18F]FDG evaluation of dementia.

BACKGROUND: Positron emission tomography/magnetic resonance imaging (PET/MRI) is a promising diagnostic imaging tool for the diagnosis of dementia, as PET can add complementary information to the routine imaging examination with MRI. The purpose of this study was to evaluate the influence of MRI-based attenuation correction (MRAC) on diagnostic assessment of dementia with [18F]FDG PET. Quantitative differences in both [18F]FDG uptake and z-scores were calculated for three clinically available (DixonNoBone, DixonBone, UTE) and two research MRAC methods (UCL, DeepUTE) compared to CT-based AC (CTAC). Furthermore, diagnoses based on visual evaluations were made by three nuclear medicine physicians and one neuroradiologist (PETCT, PETDeepUTE, PETDixonBone, PETUTE, PETCT + MRI, PETDixonBone + MRI). In addition, pons and cerebellum were compared as reference regions for normalization. RESULTS: The mean absolute difference in z-scores were smallest between MRAC and CTAC with cerebellum as reference region: 0.15 ± 0.11 σ (DeepUTE), 0.15 ± 0.12 σ (UCL), 0.23 ± 0.20 σ (DixonBone), 0.32 ± 0.28 σ (DixonNoBone), and 0.54 ± 0.40 σ (UTE). In the visual evaluation, the diagnoses agreed with PETCT in 74% (PETDeepUTE), 67% (PETDixonBone), and 70% (PETUTE) of the patients, while PETCT + MRI agreed with PETDixonBone + MRI in 89% of the patients. CONCLUSION: The MRAC research methods performed close to that of CTAC in the quantitative evaluation of [18F]FDG uptake and z-scores. Among the clinically implemented MRAC methods, DixonBone should be preferred for diagnostic assessment of dementia with [18F]FDG PET/MRI. However, as artifacts occur in DixonBone attenuation maps, they must be visually inspected to assure proper quantification.

Does inflammation precede tau aggregation in early Alzheimer's disease? A PET study.

OBJECTIVE: Our aim was to assess with positron emission tomography (PET) the temporal and spatial inter-relationships between levels of cortical microglial activation and the aggregated amyloid-ß and tau load in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). METHODS: Six clinically probable AD and 20 MCI subjects had inflammation (11C-(R)-PK11195), amyloid (11C-PiB) and tau (18F-flortaucipir) PET, magnetic resonance imaging (MRI) and a neuropsychological assessment. Parametric images of tracer binding were interrogated at a voxel level and by region of interest analyses. RESULTS: 55% of MCI and 83% of AD subjects had a high amyloid-ß load. We have previously reported that clusters of correlated amyloid and inflammation levels are present in cortex. Here we found no correlation between levels of inflammation (11C-(R)-PK11195 BPND) and tau (18F-flortaucipir SUVR) or MMSE scores in high amyloid-ß cases. INTERPRETATION: While correlated levels of amyloid-ß and inflammation can be seen in MCI, we did not detect an association between levels of cortical tau tangles and inflammation in our series of high amyloid-ß cases. High levels of inflammation could be seen in amyloid-ß positive MCI cases where 18F-flortaucipir signals were low suggesting microglial activation precedes tau tangle formation. Inflammation levels were higher in high amyloid-ß MCI than in early AD cases, compatible with it initially playing a protective role.

Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: Reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial.

Ketone bodies are neuroprotective in neurological disorders such as epilepsy. We randomly studied nine healthy human subjects twice-with and without continuous infusion of 3-hydroxybutyrate-to define potential underlying mechanisms, assessed regionally (parietal, occipital, temporal, cortical grey, and frontal) by PET scan. During 3-hydroxybutyrate infusions concentrations increased to 5.5±0.4 mmol/l and cerebral glucose utilisation decreased 14%, oxygen consumption remained unchanged, and cerebral blood flow increased 30%. We conclude that acute 3-hydroxybutyrate infusion reduces cerebral glucose uptake and increases cerebral blood flow in all measured brain regions, without detectable effects on cerebral oxygen uptake though oxygen extraction decreased. Increased oxygen supply concomitant with unchanged oxygen utilisation may contribute to the neuroprotective effects of ketone bodies.

Effect of ephedrine and phenylephrine on brain oxygenation and microcirculation in anaesthetised patients with cerebral tumours: study protocol for a randomised controlled trial.

INTRODUCTION: During brain tumour surgery, vasopressor drugs are commonly administered to increase mean arterial blood pressure with the aim of maintaining sufficient cerebral perfusion pressure. Studies of the commonly used vasopressors show that brain oxygen saturation is reduced after phenylephrine administration, but unaltered by ephedrine administration. These findings may be explained by different effects of phenylephrine and ephedrine on the cerebral microcirculation, in particular the capillary transit-time heterogeneity, which determines oxygen extraction efficacy. We hypothesised that phenylephrine is associated with an increase in capillary transit-time heterogeneity and a reduction in cerebral metabolic rate of oxygen compared with ephedrine. Using MRI and positron emission tomography (PET) as measurements in anaesthetised patients with brain tumours, this study will examine whether phenylephrine administration elevates capillary transit-time heterogeneity more than ephedrine, thereby reducing brain oxygenation. METHODS AND ANALYSIS: This is a double-blind, randomised clinical trial including 48 patients scheduled for surgical brain tumour removal. Prior to imaging and surgery, anaesthetised patients will be randomised to receive either phenylephrine or ephedrine infusion until mean arterial blood pressure increases to above 60 mm Hg or 20% above baseline. Twenty-four patients were allocated to MRI and another 24 patients to PET examination. MRI measurements include cerebral blood flow, capillary transit-time heterogeneity, cerebral blood volume, blood mean transit time, and calculated oxygen extraction fraction and cerebral metabolic rate of oxygen for negligible tissue oxygen extraction. PET measurements include cerebral metabolic rate of oxygen, cerebral blood flow and oxygen extraction fraction. Surgery is initiated after MRI/PET measurements and subdural intracranial pressure is measured. ETHICS AND DISSEMINATION: This study was approved by the Central Denmark Region Committee on Health Research Ethics (12 June 2015; 1-10-72-116-15). Results will be disseminated via peer-reviewed publication and presentation at international conferences. TRIAL REGISTRATION NUMBER: NCT02713087; Pre-results. 2015-001359-60; Pre-results.

Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease.

See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-ß have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition.

Sex differences of human cortical blood flow and energy metabolism.

Brain energy metabolism is held to reflect energy demanding processes in neuropil related to the density and activity of synapses. There is recent evidence that men have higher density of synapses in temporal cortex than women. One consequence of these differences would be different rates of cortical energy turnover and blood flow in men and women. To test the hypotheses that rates of oxygen consumption (CMRO2) and cerebral blood flow are higher in men than in women in regions of cerebral cortex, and that the differences persist with aging, we used positron emission tomography to determine cerebral blood flow and cerebral metabolic rate of oxygen as functions of age in healthy volunteers of both sexes. Cerebral metabolic rate of oxygen did not change with age for either sex and there were no differences of mean values of cerebral metabolic rate of oxygen between men and women in cerebral cortex. Women had significant decreases of cerebral blood flow as function of age in frontal and parietal lobes. Young women had significantly higher cerebral blood flow than men in frontal and temporal lobes, but these differences had disappeared at age 65. The absent sex difference of cerebral energy turnover suggests that the known differences of synaptic density between the sexes are counteracted by opposite differences of individual synaptic activity.

Washout allometric reference method (WARM) for parametric analysis of [(11)C]PIB in human brains.

Rapid clearance and disappearance of a tracer from the circulation challenges the determination of the tracer's binding potentials in brain (BP ND) by positron emission tomography (PET). This is the case for the analysis of the binding of radiolabeled [(11)C]Pittsburgh Compound B ([(11)C]PIB) to amyloid-ß (Aß) plaques in brain of patients with Alzheimer's disease (AD). To resolve the issue of rapid clearance from the circulation, we here introduce the flow-independent Washout Allometric Reference Method (WARM) for the analysis of washout and binding of [(11)C]PIB in two groups of human subjects, healthy aged control subjects (HC), and patients suffering from AD, and we compare the results to the outcome of two conventional analysis methods. We also use the rapid initial clearance to obtain a surrogate measure of the rate of cerebral blood flow (CBF), as well as a method of identifying a suitable reference region directly from the [(11)C]PIB signal. The difference of average absolute CBF values between the AD and HC groups was highly significant (P < 0.003). The CBF measures were not significantly different between the groups when normalized to cerebellar gray matter flow. Thus, when flow differences confound conventional measures of [(11)C]PIB binding, the separate estimates of CBF and BP ND provide additional information about possible AD. The results demonstrate the importance of data-driven estimation of CBF and BP ND, as well as reference region detection from the [(11)C]PIB signal. We conclude that the WARM method yields stable measures of BP ND with relative ease, using only integration for noise reduction and no model regression. The method accounts for relative flow differences in the brain tissue and yields a calibrated measure of absolute CBF directly from the [(11)C]PIB signal. Compared to conventional methods, WARM optimizes the Aß plaque load discrimination between patients with AD and healthy controls (P = 0.009).

Blood-brain transfer of Pittsburgh compound B in humans.

In the labeled form, the Pittsburgh compound B (2-(4'-{N-methyl-[(11)C]}methyl-aminophenyl)-6-hydroxy-benzothiazole, [(11)C]PiB), is used as a biomarker for positron emission tomography (PET) of brain ß-amyloid deposition in Alzheimer's disease (AD). The permeability of [(11)C]PiB in the blood-brain barrier is held to be high but the permeability-surface area product and extraction fractions in patients or healthy volunteers are not known. We used PET to determine the clearance associated with the unidrectional blood-brain transfer of [(11)C]PiB and the corresponding cerebral blood flow rates in frontal lobe, whole cerebral cortex, and cerebellum of patients with Alzheimer's disease and healthy volunteers. Regional cerebral blood flow rates differed significantly between the two groups. Thus, regional and whole-brain permeability-surface area products were identical, in agreement with the observation that numerically, but insignificantly, unidirectional blood-brain clearances are lower and extraction fractions higher in the patients. The evidence of unchanged permeability-surface area products in the patients implies that blood flow changes can be deduced from the unidirectional blood-brain clearances of [(11)C]PiB in the patients.

Low Residual CBF Variability in Alzheimer's Disease after Correction for CO(2) Effect.

We tested the claim that inter-individual CBF variability in Alzheimer's disease (AD) is substantially reduced after correction for arterial carbon dioxide tension (PaCO(2)). Specifically, we tested whether the variability of CBF in brain of patients with AD differed significantly from brain of age-matched healthy control subjects (HC). To eliminate the CO(2)-induced variability, we developed a novel and generally applicable approach to the correction of CBF for changes of PaCO(2) and applied the method to positron emission tomographic (PET) measures of CBF in AD and HC groups of subjects. After correction for the differences of CO(2) tension, the patients with AD lost the inter-individual CBF variability that continued to characterize the HC subjects. The difference (ΔK(1)) between the blood-brain clearances (K(1)) of water (the current measure of CBF) and oxygen (the current measure of oxygen clearance) was reduced globally in AD and particularly in the parietal, occipital, and temporal lobes. We then showed that oxygen gradients calculated for brain tissue were similar in AD and HC, indicating that the low residual variability of CBF in AD may be due to low functional demands for oxidative metabolism of brain tissue rather than impaired delivery of oxygen.

Brain energy metabolism and blood flow differences in healthy aging.

Cerebral metabolic rate of oxygen consumption (CMRO(2)), cerebral blood flow (CBF), and oxygen extraction fraction (OEF) are important indices of healthy aging of the brain. Although a frequent topic of study, changes of CBF and CMRO(2) during normal aging are still controversial, as some authors find decreases of both CBF and CMRO(2) but increased OEF, while others find no change, and yet other find divergent changes. In this reanalysis of previously published results from positron emission tomography of healthy volunteers, we determined CMRO(2) and CBF in 66 healthy volunteers aged 21 to 81 years. The magnitudes of CMRO(2) and CBF declined in large parts of the cerebral cortex, including association areas, but the primary motor and sensory areas were relatively spared. We found significant increases of OEF in frontal and parietal cortices, excluding primary motor and somatosensory regions, and in the temporal cortex. Because of the inverse relation between OEF and capillary oxygen tension, increased OEF can compromise oxygen delivery to neurons, with possible perturbation of energy turnover. The results establish a possible mechanism of progression from healthy to unhealthy brain aging, as the regions most affected by age are the areas that are most vulnerable to neurodegeneration.

Glucose metabolism in small subcortical structures in Parkinson's disease.

OBJECTIVES: Evidence from experimental animal models of Parkinson's disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high-resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei. MATERIALS AND METHODS: Using the HRRT, we performed [(18)F]-fluorodeoxyglucose (FDG) scans on 21 patients with PD and 11 age-matched controls. We employed three types of normalization: white matter, global mean, and data-driven normalization. We performed volume-of-interest analyses of small subcortical gray matter structures. Voxel-based comparisons were performed to investigate the extent of cortical hypometabolism. RESULTS: The most significant level of relative subcortical hypermetabolism was detected in the external pallidum (GPe), irrespective of normalization strategy. Hypermetabolism was suggested also in the internal pallidum, thalamic subnuclei, and the putamen. Widespread cortical hypometabolism was seen in a pattern very similar to previously reported patterns in patients with PD. CONCLUSION: The presence and extent of subcortical hypermetabolism in PD is dependent on type of normalization. However, the present findings suggest that PD, in addition to widespread cortical hypometabolism, is probably characterized by true hypermetabolism in the GPe. This finding was predicted by the animal 2-deoxyglucose autoradiography literature, in which high-magnitude hypermetabolism was also most robustly detected in the GPe.

Variable ATP yields and uncoupling of oxygen consumption in human brain.

The distribution of brain oxidative metabolism values among healthy humans is astoundingly wide for a measure that reflects normal brain function and is known to change very little with most changes of brain function. It is possible that the part of the oxygen consumption rate that is coupled to ATP turnover is the same in all healthy human brains, with different degrees of uncoupling explaining the variability of total oxygen consumption among people. To test the hypothesis that about 75% of the average total oxygen consumption of human brains is common to all individuals, we determined the variability in a large group of normal healthy adults. To establish the degree of variability in different regions of the brain, we measured the regional cerebral metabolic rate for oxygen in 50 healthy volunteers aged 21-66 and projected the values to a common age of 25.Within each subject and region, we normalized the metabolic rate to the population average of that region. Coefficients of variation ranged from 10 to 15% in the different regions of the human brain and the normalized regional metabolic rates ranged from 70% to 140% of the population average for each region, equal to a two-fold variation. Thus the hypothetical threshold of oxygen metabolism coupled to ATP turnover in all subjects is no more than 70% of the average oxygen consumption of that population.

Subcortical elevation of metabolism in Parkinson's disease--a critical reappraisal in the context of global mean normalization.

In a recent issue of NeuroImage, we presented evidence that biased global mean (GM) normalization of brain PET data can generate the appearance of subcortical foci with relative hypermetabolism in patients with Parkinson's disease (PD), and other degenerative disorders. In a commentary to our article, Ma and colleagues presented a study seeking to establish that a pattern of widespread hypermetabolism, known as the Parkinson's disease related pattern (PDRP) is a genuine metabolic feature of PD. In the present paper, we respond to the arguments presented by Ma et al., and we provide a critical reappraisal of the evidence for the existence of the PDRP. To this end, we present new analyses of PET data sets, which demonstrate that very similar patterns of relative subcortical increases are seen in PD, Alzheimer's disease, hepatic encephalopathy, healthy aging, and simulation data. Furthermore, longitudinal studies of PD previously reported relative hypermetabolism in very small anatomical structures such as the subthalamic nucleus. We now demonstrate how focal hypermetabolism attributed to small nuclei can similarly arise as a consequence of GM normalization. Finally, we give a comprehensive summary of the entire deoxyglucose autoradiography literature on acquired parkinsonism in experimental animals. Based on this evidence, we conclude that (1) there is no quantitative evidence for widespread subcortical hypermetabolism in PD, (2) very similar patterns of subcortical hyperactivity are evident in various other brain disorders whenever GM normalization is utilized, and (3) the PDRP is not evident in animal models of PD. In the absence of quantitative evidence for the PDRP, our alternative interpretation of normalization bias seems the more parsimonious explanation for the reports of relative hypermetabolism in PD.

Data-driven intensity normalization of PET group comparison studies is superior to global mean normalization.

BACKGROUND: Global mean (GM) normalization is one of the most commonly used methods of normalization in PET and SPECT group comparison studies of neurodegenerative disorders. It requires that no between-group GM difference is present, which may be strongly violated in neurodegenerative disorders. Importantly, such GM differences often elude detection due to the large intrinsic variance in absolute values of cerebral blood flow or glucose consumption. Alternative methods of normalization are needed for this type of data. MATERIALS AND METHODS: Two types of simulation were performed using CBF images from 49 controls. Two homogeneous groups of 20 subjects were sampled repeatedly. In one group, cortical CBF was artificially decreased moderately (simulation I) or slightly (simulation II). The other group served as controls. Ratio normalization was performed using five reference regions: (1) Global mean; (2) An unbiased VOI; (3) Data-driven region extraction (Andersson); (4-5) Reference cluster methods (Yakushev et al.). Using voxel-based statistics, it was determined how much of the original signal was detected following each type of normalization. RESULTS: For both simulations, global mean normalization performed poorly, with only a few percent of the original signal recovered. Global mean normalization moreover created artificial increases. In contrast, the data-driven reference cluster method detected 65-95% of the original signal. CONCLUSION: In the present simulation, the reference cluster method was superior to GM normalization. We conclude that the reference cluster method will likely yield more accurate results in the study of patients with early to moderate stage neurodegenerative disorders.