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Background: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer's disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis., Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus., Methods: Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®) = 0, amyloid β (Aβ)-negative, n = 34]; Preclinical AD (CDR = 0, Aβ-positive, n = 19); and mild AD (CDR = 0.5 or 1, Aβ-positive, n = 17)., Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as "Dark Matter", and the other, with relatively preserved neurons, "Viable Tissue". Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration., Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.

A hallmark of non-rapid eye movement (REM) sleep is the decreased brain activity as measured by global reductions in cerebral blood flow, oxygen metabolism, and glucose metabolism. It is unknown whether the blood oxygen level dependent (BOLD) signal undergoes similar changes. Here we show that, in contrast to the decreases in blood flow and metabolism, the mean global BOLD signal increases with sleep depth in a regionally non-uniform manner throughout gray matter. We relate our findings to the circulatory and metabolic processes influencing the BOLD signal and conclude that because oxygen consumption decreases proportionately more than blood flow in sleep, the resulting decrease in paramagnetic deoxyhemoglobin accounts for the increase in mean global BOLD signal.

Glucose and oxygen metabolism are tightly coupled in the human brain, with the preponderance of the brain's glucose supply used to generate ATP via oxidative phosphorylation. A fraction of glucose is consumed outside of oxidative phosphorylation despite the presence of sufficient oxygen to do so. We refer to this process as aerobic glycolysis. A recent positron emission tomography study reported that aerobic glycolysis is uniform within gray matter. Here, we analyze the same data and demonstrate robust regional differences in aerobic glycolysis within gray matter, a finding consistent with previously published data.

Positron emission tomography (PET) with 15 O-tracers is commonly used to measure brain hemodynamic parameters such as cerebral blood flow, cerebral blood volume, and cerebral metabolic rate of oxygen. Conventionally, the absolute quantification of these parameters requires an arterial input function that is obtained invasively by sampling blood from an artery. In this work, we developed and validated an image-derived arterial input function technique that avoids the unreliable and burdensome arterial sampling procedure for full quantitative 15 O-PET imaging. We then compared hemodynamic PET imaging performed on a PET/MR hybrid scanner against a conventional PET only scanner. We demonstrated the proposed imaging-based technique was able to generate brain hemodynamic parameter measurements in strong agreement with the traditional arterial sampling based approach. We also demonstrated that quantitative 15 O-PET imaging can be successfully implemented on a PET/MR hybrid scanner.

Positron emission tomography (PET) with (15)O-labeled water can provide reliable measurement of cerebral blood flow (CBF). Quantification of CBF requires knowledge of the arterial input function (AIF), which is usually provided by arterial blood sampling. However, arterial sampling is invasive. Moreover, the blood generally is sampled at the wrist, which does not perfectly represent the AIF of the brain, because of the effects of delay and dispersion. We developed and validated a new noninvasive method to obtain the AIF directly by PET imaging of the internal carotid artery in a region of interest (ROI) defined by coregistered high-resolution magnetic resonance angiography. An ROI centered at the petrous portion of the internal carotid artery was defined, and the AIF was estimated simultaneously with whole brain blood flow. The image-derived AIF (IDAIF) method was validated against conventional arterial sampling. The IDAIF generated highly reproducible CBF estimations, generally in good agreement with the conventional technique.

Functional imaging of a language task using positron emission tomography was performed as part of the preoperative assessment of a patient with a left supplementary motor area (SMA) tumor. Positron emission tomography scans were obtained during language tasks (verb generation and word reading of visually presented nouns) that normally lead to increased blood flow in the SMA relative to a control condition (visual fixation). In the patient, the normal SMA response was an order of magnitude larger in the region of the tumor. Other regions, such as left inferior frontal cortex and right cerebellum, showed equivalent activation in the patient and normal subjects. Histopathologic study revealed an anaplastic astrocytoma. Thus, this exaggerated vascular response to local neuronal activation occurred in the setting of a proliferation of glial cells. This is consistent with models of coupling of regional CBF and neuronal activity that implicate glia as the mediator between neurons and vasculature. The concept that tumoral disruption of normal vascular responses could, in some cases, potentially enhance rather than dampen the response is proposed.

To further our understanding of the best way to measure regional CBF with positron emission tomography (PET), we directly compared two candidate tracers ([15O]water and [11C]butanol, administered intravenously) and two popular implementations of the one-compartment (1C) model: the autoradiographic implementation representing a single PET measurement of tissue radioactivity over 1 min and a dynamic implementation representing a sequence of measurements of tissue radioactivity over 200 s. We also examined the feasibility of implementing a more realistic, and thus more complex, distributed-parameter (DP) model by assigning fixed values for all of its parameters other than CBF and tracer volume of distribution (Vd), a requirement imposed by the low temporal resolution and statistical quality of PET data. The studies were performed in three normal adult human subjects during paired rest and visual stimulation. In each subject seven regions of interest (ROIs) were selected, one of which was the primary visual cortex. The corresponding ROI were anatomically equivalent in the three subjects. Regional CBF, Vd, tracer arrival delay, and dispersion were estimated for the dynamic data curves. A total of 252 parameter sets were estimated. With [11C]butanol both implementations of the 1C model provided similar results (r = 0.97). Flows estimated using the 1C models were lower (p < 0.01) with [15O]water than with [11C]butanol. In comparison with the 1C model, the constrained version of the DP used in these studies performed inadequately, overestimating high flow and underestimating low flow with both tracers, possibly as the result of the necessity of assigning fixed values for all of its parameters other than CBF and Vd.

We have revised our methods for calculating regional blood volume, flow, oxygen extraction, and oxygen utilization from positron emission tomography data obtained using 15O-labeled radiotracers. These revisions include radioactive decay explicitly within the model equations instead of requiring all measured activity to be corrected for decay prior to incorporation in the equations. The revised equations yield small but significant differences in the computed values.

A new "mean regional" method for calculating global hemispheric values of blood flow, blood volume, and metabolism with positron emission tomography is presented. It is based on a standardized set of regions defined according to coordinates in a stereotactic atlas of the brain. Region locations in each individual scan were determined by a localization technique that is independent of the appearance of the physiological images. Measurements obtained with this mean regional method minimize contributions from nonbrain structures such as ventricles or venous sinuses and provide the necessary basis for comparisons among different subjects and laboratories.

Intersubject averaging and change-distribution analysis of subtracted positron emission tomographic (PET) images were developed and tested. The purpose of these techniques is to increase the sensitivity and objectivity of functional mapping of the human brain with PET. To permit image averaging, all primary tomographic images were converted to anatomically standardized three-dimensional images using stereotactic anatomical localization and interslice interpolation. Image noise, measured in control-minus-control subtractions, was strongly suppressed by averaging. Signal-to-noise ratio, measured in stimulus-minus-control subtractions (hand vibration minus eyes-closed rest), rose steadily with averaging, confirming the accuracy of our method of anatomical standardization. Distribution analysis of CBF change images (outlier detection by gamma-2 statistic) was assessed as an omnibus test for state-dependent changes in regional neuronal activity. Sensitivity in detecting the somatosensory response rose steadily with averaging, increasing from 50% in individual images to 100% when three or more images were averaged. Specificity was 100% at all averaging levels. Although described here as a technique for functional brain mapping with H2(15O) CBF images, image averaging, and change-distribution analysis are more generally applicable techniques, not limited to a single purpose or tracer.

Functional mapping of the human brain with positron emission tomography (PET) can best be performed by obtaining multiple short measurements of cerebral blood flow in a single sitting. In this manner regional changes in blood flow accompanying the increased neuronal activity from a movement, sensation, or even cognition task, have been identified. However, localizing a functional region with PET has been severely limited by the poor resolving properties of PET devices. Using a new method of data analysis we recently reported the mapping of visual field stimuli on human visual cortex with surprisingly high reliability as measured by the low standard deviation in positions across different subjects (as low as 1 mm). In this work the analysis technique enabling such high-resolution functional brain mapping is fully described. Additionally, simulations are presented to illustrate its advantages and limitations.

Dopaminergic ligands labeled with positron-emitting radionuclides have been synthesized for quantitative evaluation of dopaminergic binding in vivo. Two different methods, the explicit method and an operationally simplified ratio method, have been proposed for analysis of these positron emission tomographic (PET) data. The basis for both methods is the same three-compartment model. The two methods differ in the assumptions necessary for practical implementation. We have compared these two approaches using PET data obtained in our laboratory. Sequential scans and serial arterial blood samples from a baboon following intravenous injection of [18F]spiroperidol were collected. Application of the two methods to the same data yielded different values for corresponding parameters. Values calculated by the ratio method for the specific rate constant describing receptor binding varied depending upon the time after tracer injection, thus demonstrating an internal inconsistency in this approach. Tracer metabolism markedly affected the binding measurements calculated with either method and thus cannot be ignored. Our results indicate that the adoption of simplifying assumptions for operational convenience can lead to substantial errors and must be done with caution. Alternatively, we present simple new analytical solutions of the tracer conservation equations describing the complete, unsimplified three-compartment model that vastly reduce the computations necessary to implement the explicit method.

We have previously adapted Kety's tissue autoradiographic method for measuring regional CBF in laboratory animals to the measurement of CBF in humans with positron emission tomography (PET) and H2(15)O. Because this model assumes diffusion equilibrium between tissue and venous blood, the use of a diffusion-limited tracer, such as H2(15)O, may lead to an underestimation of CBF. We therefore validated the use of [11C]butanol as an alternative freely diffusible tracer for PET. We then used it in humans to determine the underestimation of CBF that occurs with H2(15)O, and thereby were able to calculate the extraction Ew and permeability-surface area product PSw of H2(15)O. Measurements of the permeability of rhesus monkey brain to [11C]butanol, obtained by means of an intracarotid injection, external detection technique, demonstrated that this tracer is freely diffusible up to a CBF of at least 170 ml/min-100 g. CBF measured in baboons with the PET autoradiographic method and [11C]butanol was then compared with CBF measured in the same animals with a standard residue detection method. An excellent correspondence was obtained between both of these measurements. Finally, paired PET measurements of CBF were made with both H2(15)O and [11C]butanol in 17 normal human subjects. Average global CBF was significantly greater when measured with [11C]butanol (53.1 ml/min-100 g) than with H2(15)O (44.4 ml/min-100 g). Average global Ew was 0.84 and global PSw was 104 ml/min-100 g. Regional measurements showed a linear relationship between local PSw and CBF, while Ew was relatively uniform throughout the brain. Simulations were used to determine the potential error associated with the use of an incorrect value for the brain-blood partition coefficient for [11C]butanol and to calculate the effect of tissue heterogeneity and errors in flow measurement on the calculation of PSw.

The equilibrium C15O2 inhalation method for measuring cerebral blood flow with positron emission tomography (PET) is based on a one-compartment model for which it is assumed that the local flow and partition coefficient are uniform in the tissue region in which flow is to be determined. However, because of the limited spatial resolution of PET, a region of interest will contain a mixture of gray and white matter. We used a computer simulation to examine the effect of this heterogeneity on flow measurement in both normal and pathological states. With gray and white matter flows of 0.80 and 0.20 ml/min/g, respectively, flow is underestimated by a maximum of 20% in a region that is 30% gray. Errors occur not only because of flow heterogeneity, but also because of heterogeneity of partition coefficient and the sensitivity of the method to errors in partition coefficient. Larger errors occur in the case of cerebral hyperemia, although the method becomes more accurate with ischemia. In the case of simulated brain tumor, the accuracy of flow determination varies considerably, depending on the flow and partition coefficient of the tumor and of the surrounding tissue. Finally, incremental changes in gray matter flow, as would occur with functional cortical activation, are not well reflected. Thus, the equilibrium C15O2 inhalation method is limited in its ability to accurately quantitate local cerebral blood flow in heterogeneous tissue regions.

A knowledge of the brain-blood partition coefficient (lambda) for water is usually required for the measurement of CBF with [15O]water. The currently accepted value for whole-brain lambda, 0.95-0.96 ml/g, calculated from brain and blood water content data, is incorrect because in the calculation, the blood water content was not adjusted for the density of blood. The correct value is 0.90 ml/g. Variations in brain or blood water content affect lambda. Thus, lambda changes during development of the brain and varies regionally in it, even among different gray matter structures, owing to variation in brain water content. In addition, lambda would be expected to vary with the hematocrit, owing to changes in blood water content. The impact of using an incorrect value for lambda will depend on the sensitivity of the CBF measurement technique used to errors in lambda.

Given the low spatial resolution of positron emission tomography (PET), regional measurements of neural tissue are often inaccurate because of the presence of non-neural elements and to mixtures of different tissue types within the volume of space influencing the measurements. These effects are significant in scans of brains both with and without atrophy, but are particularly significant when comparing measurements of brains with atrophy with those of normals, as is typically done in studies of aging and dementia. Previous attempts to correct for cerebral atrophy have been limited to global measurements. Using computer simulations, we illustrate the effects of atrophy and describe a method for correcting regional PET data to represent units of actual neural tissue volume.

All tracer-kinetic models currently employed with positron-emission tomography (PET) are based on compartmental assumptions. Our first indication that a compartmental model might suffer from severe limitations in certain circumstances when used with PET occurred when we implemented the Kety tissue-autoradiography technique for measuring CBF and observed that the resulting CBF estimates, rather than remaining constant (to within predictable statistical uncertainty) as expected, fell with increasing scan duration T when T greater than 1 min. After ruling out other explanations, we concluded that a one-compartment model does not possess sufficient realism for adequately describing the movement of labeled water in brain. This article recounts our search for more realistic substitute models. We give our derivations and results for the residue-detection impulse responses for unit capillary-tissue systems of our two candidate distributed-parameter models. In a sequence of trials beginning with the simplest, we tested four progressively more detailed candidate models against data from appropriate residue-detection experiments. In these, we generated high-temporal-resolution counting-rate data reflecting the history of radiolabeled-water uptake and washout in the brains of rhesus monkeys. We describe our treatment of the data to yield model-independent empirical values of CBF and of other parameters. By substituting these into our trial-model functions, we were able to make direct comparisons of the model predictions with the experimental dynamic counting-rate histories, confirming that our reservations concerning the one-compartment model were well founded and obliging us to reject two others. We conclude that a two-barrier distributed-parameter model has the potential of serving as a substitute for the Kety model in PET measurements of CBF in patients, especially when scan durations for T greater than 1 min are desired.

Because positron emission tomography (PET) provides measurements per unit volume of intracranial contents, these measurements may be affected by the inclusion of metabolically inactive CSF spaces in the volume in which they are made. Thus, PET measurements of CBF and metabolism may be artifactually lowered in normal aging and dementia, which are both associated with significant brain atrophy. We describe a method to correct global PET data, averaged over several tomographic slices, for cerebral atrophy by using measurements of CSF space volume obtained with quantitative x-ray computed tomography. The importance of making such a correction is demonstrated using PET measurements of CBF and oxygen metabolism obtained in normal young, normal elderly, and demented subjects.

An intravenous injection method to measure cerebral vascular extraction fractions of highly diffusible substances in the rat is described. The brain extraction fractions of 3H-labeled water (Ew) and ethanol (Ee) were defined as the ratio of either of those tracers to the freely diffusible reference tracer, 14C-butanol, in the brain, divided by the ratio of the tracers available for the extraction during the time between simultaneous intravenous injection of the tracers and decapitation of the rat. Ew and Ee were measured in five regions of brain, including brainstem and cerebellum, under PaCO2 conditions ranging from 15 to 85 mm Hg. The extraction fractions for both test tracers were shown to vary with PaCO2-induced flow changes according to the equation, ln(1 - E) = -PS/F. When PS/F values calculated from regional measurements of Ew and Ee were plotted versus PaCO2, least squares regression equations of the plots could be used to compare permeabilities of both tracers at any given PaCO2 value. Ratios of the permeabilities of water and ethanol varied regionally but were relatively constant in a given region under different flow states. This intravenous injection method allows for accurate measurement of the extraction fractions of even highly diffusible tracers under varied flow conditions in all brain regions regardless of arterial blood supply.

This study was undertaken to determine the minimum CBF and CMRO2 required by the human brain to maintain normal function and viability for more than a few hours. Positron emission tomography (PET) was used to perform regional measurements in 50 subjects with varying degrees of cerebral ischemia but no evidence of infarction. There were 24 normal subjects, 24 subjects with arteriographic evidence of vascular disease of the carotid system, and two subjects with reversible ischemic neurological deficits due to cerebral vasospasm. Minimum values found in the 48 subjects with normal neurological function were 19 ml/100 g-min for regional cerebral blood flow (rCBF) and 1.3 ml/100 g-min for regional cerebral metabolic rate of oxygen (rCMRO2). Minimum values for all 50 subjects with viable cerebral tissue were 15 ml/100 g-min for rCBF and 1.3 ml/100 g-min for rCMRO2. Comparison of these measurements with values from 20 areas of established cerebral infarction in 10 subjects demonstrated that 80% (16/20) of infarcted regions had rCMRO2 values below the lower normal limit of 1.3 ml/100 g-min. Measurements of rCBF, regional cerebral blood volume, and oxygen extraction fraction were less useful for distinguishing viable from infarcted tissue. These data indicate that quantitative regional measurements of rCMRO2 with PET accurately distinguish viable from nonviable cerebral tissue and may be useful in the prospective identification of patients with reversible ischemia.

Local cerebral blood volume (CBV) has been measured previously with inhaled 11CO and positron emission tomography (PET). The model used assumes that equilibrium in tracer concentration has occurred between arterial and systemic venous blood before the PET measurement is made. To verify that this model may be used with the much shorter half-lived C15O, we have simultaneously measured arterial and venous blood radioactivity following C15O inhalation. Equilibrium occurred 95 +/- 39 s after inhalation (n = 7). If the PET measurement is commenced prior to arteriovenous equilibrium, significant errors occur in calculated CBV. These data indicate that C15O may be used as a tracer for CBV measurement provided that emission data collection commences at approximately 120 s after inhalation. Strict quality control measures must be maintained to minimize the contamination of administered C15O with 15O-labeled CO2.

Positron emission tomography (PET) and 15O-labeled radiotracers were used to measure regional CBF, cerebral blood volume (CBV), CMRO2, and oxygen extraction in 32 right-handed subjects at rest. Mean left hemispheric CBF (46.2 +/- 6.8 ml/100 g/min) and CMRO2 (2.60 +/- 0.59 ml/100 g/min) were significantly lower than right hemispheric values (47.4 +/- 7.2 and 2.66 +/- 0.61 ml/100 g/min, respectively; p less than 0.0001 for both), whereas left and right hemispheric CBV and oxygen extraction were not significantly different. We further investigated these asymmetries by comparing left- and right-sided values for specific cortical and subcortical regions. We found that left-sided CBF and CMRO2 were significantly lower than right-sided values for sensorimotor, occipital, and superior temporal regions, whereas only left-sided CBF values were lower for anterior cingulum. CBV was asymmetric for the anterior cingulate and mid-frontal regions, and oxygen extraction was asymmetric for the sensorimotor area. No asymmetries were observed in inferior parietal cortex, thalamus, putamen, or pallidum. Knowledge of these normal physiological asymmetries is essential for proper interpretation of PET studies of physiology and pathology. Furthermore, the ability to detect asymmetries with PET may lead to a better understanding of the lateralization of specific functions in the human brain.

Positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) with intravenously administered 15O-labeled water and an adaptation of the Kety autoradiographic model are well suited to the study of functional-anatomical correlations within the human brain. This model requires arterial blood sampling to determine rCBF from the regional tissue radiotracer concentration (Cr) recorded by the tomograph. Based upon the well-defined, nearly linear relation between Cr and rCBF inherent in the model, we have developed a method for estimating changes in rCBF from changes in Cr without calculating true rCBF and thus without arterial sampling. This study demonstrates that quantitative functional brain mapping does not require the determination of rCBF from Cr when regional neuronal activation is expressed as the change in rCBF from an initial, resting-state measurement. Patterned-flash visual stimulation was used to produce a wide range of increases in rCBF within the striate cortex. Changes in occipital rCBF were found to be accurately estimated directly from Cr over a series of 56 measurements on eight subjects. This adaptation of the PET/autoradiographic method serves to simplify its application and to make it more acceptable to the subject.