Noninvasive measurement of myocardial blood flow in absolute terms (i.e., milliliters per gram per min) has been difficult to accomplish despite the intrinsically quantitative power of positron emission tomography because of the nonphysiologic nature of tracers that have been employed conventionally as well as the limited spatial resolution of currently available instruments. It was previously demonstrated that myocardial blood flow in animals can be quantitated accurately with the diffusible tracer oxygen-15-labeled water (H2(15)O) when the arterial input function and myocardial radiotracer concentration were measured directly. To extend the approach for completely noninvasive measurement of blood flow, a parameter estimation procedure was developed whereby effects of limited tomographic spatial resolution and cardiac motion were compensated for within the operational flow model. In validation studies in 18 dogs, myocardial blood flow measured with positron emission tomography after intravenously administered H2(15)O correlated closely with flow measured with concomitantly administered radiolabeled microspheres over the range of 0.29 to 5.04 ml/g per min (r = 0.95). Although regional ischemia was clearly identifiable tomographically, absolute flow could not be determined accurately in ischemic regions in four dogs because of poor count statistics related to wall thinning. Subsequently, myocardial blood flow was measured in 11 normal human subjects. Flow was homogeneous throughout the myocardium, averaged 0.90 +/- 0.22 ml/g per min at rest and increased to 3.55 +/- 1.15 ml/g per min after intravenous administration of dipyridamole. Therefore, positron emission tomography with H2 15O and the approach developed permits noninvasive measurement of myocardial blood flow in absolute terms in humans and should facilitate objective assessment of interventions designed to enhance nutritive perfusion.

Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntington's disease (HD) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO2/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO2/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 ؎ 1.6 vs. 5.1 ؎ 0.9, P ‫؍‬ 0.04). CMRO2 was not different from controls (126 ؎ 37 vs. 134 ؎ 31 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.49), whereas CMRglc was decreased (21.6 ؎ 6.1 vs. 26.4 ؎ 4.6 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.01). Striatal volume was decreased as well (13.9 ؎ 3.5 vs. 17.6 ؎ 2.0 ml, P ‫؍‬ 0.001). Increased striatal CMRO2/CMRglc with unchanged CMRO2 is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HD. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HD.cerebral metabolism ͉ mitochondria ͉ oxidative phosphorylation ͉ basal ganglia H untington's disease (HD) is a degenerative neurological disease that is manifested by abnormal involuntary movements, psychiatric disorders, and dementia. It has a variable age at onset and progresses slowly to death 15-25 years after symptoms develop. HD is neuropathologically characterized by early selective loss of medium spiny neurons in striatum (caudate and putamen) with later neuronal loss in cortex, globus pallidus, and other structures. Although it is now known that an expansion of the triple repeat CAG in the IT15 gene on chromosome 4 leads to production of an abnormal polyglutamine string on the huntingtin protein, it is still unclear how this leads to selective neuronal cell death (1). In postmortem specimens from the striatum of patients with HD, reduced activity of the mitochondrial electron transport system (ETS) (29-76% decreases in complexes II and III and 30-62% decreases in complex IV) has been measured in vitro, although these findings have not been universal (2-6). These findings and the correlative effects of mitochondrial toxins in producing striatal neuronal loss in animal models suggest that excitotoxicity triggered by reduced ATP production as a consequence of impaired mitochondrial oxidative phosphorylation may be an important mechanism for neuronal death in HD (7). Alternatively, these mitochondrial changes may be ...

Using H,15O (half-

In this study we have investigated the pathophysiology of two idiopathic focal dystonias: hand cramp with excessive cocontractions of agonist and antagonist hand or forearm muscles during specific tasks, such as writing, and facial dystonia manifested by involuntary eyelid spasms (blepharospasm) and lower facial and jaw spasms (oromandibular dystonia). We used positron emission tomography (PET) to measure the in vivo binding of the dopaminergic radioligand [18F]spiperone in putamen in 21 patients with these two focal dystonias and compared the findings with those from 13 normals. We measured regional cerebral blood flow and blood volume in each subject as well as the radiolabeled metabolites of [18F]spiperone in arterial blood. A stereotactic method of localization, independent of the appearance of the images, was used to identify the putamen in all of the PET images. We analyzed the PET and arterial blood data with a validated nonsteady-state tracer kinetic model representing the in vivo behavior of the radioligand. An index of binding called the combined forward rate constant was decreased by 29% in dystonics, as compared with normals (p < 0.05). There were no significant differences between dystonics and normals in regional blood flow, blood volume, nonspecific binding, permeability-surface area product of [18F]spiperone or the dissociation rate constant. These findings are consistent with a decrease of dopamine D2-like binding in putamen and are the first demonstration of a receptor abnormality in idiopathic dystonia. These results have important implications for the pathophysiology of dystonia as well as for function of the basal ganglia.

Summary: 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 limita tions in certain circumstances when used with PET oc curred when we implemented the Kety tissue-autoradiog raphy technique for measuring CBF and observed that the resulting CBF estimates, rather than remaining con stant (to within predictable statistical uncertainty) as ex pected, fe ll with increasing scan duration T when T > 1 min . After ruling out other explanations, we concluded that a one-compartment model does not possess suffi cient realism for adequately describing the movement of labeled water in brain. This article recounts our search for more realistic substitute models. We give our deriva tions and results for the residue-detection impulse re sponses for unit capillary-tissue systems of our two can didate distributed-parameter models. In a sequence of trials beginning with the simplest, we tested fo ur progres-The measurement of CBF is important not only because of the information it provides about the normal and diseased brain, but also because it is essential to other important measurements (e.g. , rate of oxygen consumption). Tr acer-kinetic models are employed with external radiation-detection de vices to interpret dynamic imaging data in terms of the movements of radiolabeled water (H 2 1 50) or other diffusible tracer (e.g. , [ 1 8F] fluoromethane) for the purpose of inferring CBF. The tracer-kinetic model currently employed with positron-emission tomography (PET) for this purpose is based on 443sively more detailed candidate models against data fr om appropriate residue-detection experiments. In these, we generated high-temporal-resolution counting-rate data re flecting 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 em pirical values of CBF and of other parameters. By substi tuting these into our trial-model fu nctions , we were able to make direct comparisons of the model predictions with the experimental dynamic counting-rate histories, con firming that our reservations concerning the one-com partment model were well founded and obliging us to re ject two others . We conclude that a two-barrier distrib uted-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> 1 min are desired. Key Words: Cerebral blood flow-Dis tributed-parameter models-Po sitron-emission tomog raphy-Tissue heterogeneity-Tr acer kinetics. compartmental assumptions; that is , tracer is as sumed to move between discrete subvolumes, or "compartments," within each of which tracer is assumed to distribute instantaneously upon arrival. Thus, in a compartmental model, gradients of con centration are assumed to be zero (i.e. , their spatial profiles flat) within each compartment at all times. The compartmental mode...

A B S T R A C T The role of the kidney in the metabolism of parathyroid hormone (PTH) was examined in the dog. Studies were performed in awake normal and uremic dogs after administration of bovine parathyroid hormone (b-PTH) or synthetic amino terminal tetratricontapeptide of b-PTH (syn b-PTH 1-34). The renal clearance of immunoreactive PTH was determined from the product of renal plasma flow and the percent extraction of PTH immunoreactivity by the kidney. Blood levels of circulating immunoreactive PTH were determined by radioimmunoassay.The normal dog kidney extracted 20±1% of the immunoreactive b-PTH delivered to it, and renal clearance (RC) of immunoreactivity was 60 ml/min. When RC was compared to an estimate of total metabolic clearance (MCR) of immunoreactivity, it accounted for 61% of the total. Both MCR and RC were markedly decreased in dogs with chronic renal disease. However, the percent extraction of immunoreactive PTH was unchanged in chronic renal disease, and the observed decrease in RC was due to changes in renal plasma flow. The largest portion of the reduction in total MCR was accounted for by the decrease in RC, and there was no compensation for the decrease in RC by extrarenal sites of PTH metabolism.

Cerebral perfusion imaging using dynamic susceptibility contrast (DSC) has been the subject of considerable research and shows promise for basic science and clinical use. In DSC, the MRI signals in brain tissue and feeding arteries are monitored dynamically in response to a bolus injection of paramagnetic agents, such as gadolinium (Gd) chelates. DSC has the potential to allow quantitative imaging of parameters such as cerebral blood flow (CBF) with a high signal‐to‐noise ratio (SNR) in a short scan time; however, quantitation depends critically on accurate and precise measurement of the arterial input function (AIF). We discuss many requirements and factors that make it difficult to measure the AIF. The AIF signal should be linear with respect to Gd concentration, convertible to the same concentration scale as the tissue signal, and independent of hematocrit. Complicated relationships between signal and concentration can violate these requirements. The additional requirements of a high SNR and high spatial/temporal resolution are technically challenging. AIF measurements can also be affected by signal saturation and aliasing, as well as dispersion/delay between the AIF sampling site and the tissue. We present new in vivo preliminary results for magnitude‐based (ΔR2*) and phase‐based (Δϕ) AIF measurements that show a linearity advantage of phase, and a disparity in the scaling of Δϕ AIFs, ΔR2* AIFs, and ΔR2* tissue curves. Finally, we discuss issues related to the choice of AIF signal for quantitative perfusion imaging. J. Magn. Reson. Imaging 2005. © 2005 Wiley‐Liss, Inc.

Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after ϳ24 h of interprandial hypoglycemia (ϳ55 mg/dl, ϳ3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P ‫؍‬ 0.009), neurogenic symptoms (P ‫؍‬ 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose metabolism were calculated from rate constants derived from blood and brain timeactivity curves-the latter determined by positron emission tomography (PET)-after intravenous injection of [1- , respectively), cerebral glucose metabolism (16.8 ؎ 0.9 and 15.9 ؎ 0.9 mol ⅐ 100 g ؊1 ⅐ min ؊1 , respectively) and cerebral blood flow (56.8 ؎ 3.9 and 53.3 ؎ 4.4 ml ⅐ 100 g ؊1 ⅐ min ؊1 , respectively) were virtually identical. These data do not support the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport during subsequent hypoglycemia. They do not exclude regional increments in blood-to-brain glucose transport. Alternatively, the fundamental alteration might lie beyond the blood-brain barrier.