The spectral signature method for the analysis of PET brain images

We introduce the concept of the metabolic centroid spectrum as the feature space to characterize the distribution of metabolic activity in three-dimensional brains. The method computes the metabolic centroid of a brain subvolume for each increment of metabolic activity occurring in the whole brain. The result is the metabolic spectral signature, a continuous three-dimensional curve whose shape reflects the distribution of metabolic rates in the brain. The method's sensitivity to metabolic distribution asymmetries is greatly increased over that of the metabolic centroid method, while retaining its advantages; it is almost invariant to head size, head positioning, photon scatter, and the positron emission tomography (PET) camera's full width at half-maximum. It does not require magnetic resonance, computed tomography, or x-ray images. To test the method we analyzed the metabolic PET images of 40 normal subjects and 20 schizophrenics. The results show a unification of several metabolic characteristics of schizophrenic brains, such as laterality, hypofrontality, cortical/subcortical abnormalities, and overall brain hypometabolism, which were identified by different laboratories in separate studies using differing methodologies. Here they are presented by a single automatic objective method.     

Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure

BACKGROUND: Chronic renal failure (CRF) is associated with an atherogenic lipid profile and an increased risk of ischaemic cardiovascular disease. The associated hyperlipidaemia is reportedly ameliorated by erythropoietin (Epo) therapy. According to a recent report, rats studied 3 weeks after 5/6 nephrectomy and fed a high- protein diet exhibited increased activities of hepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase (Ch-7 alpha- H), despite normal corresponding mRNA values. DESIGN AND METHODS: This study was designed to examine the effects of naturally progressing CRF of longer duration as well as those of Epo therapy on gene expressions of the key factors involved in hepatic cholesterol metabolism, i.e., LDL receptor (LDLR), HMG-CoAR, and Ch-7 alpha-H. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy), Epo-treated CRF group (given Epo 150 U/kg/twice weekly) and sham-operated, placebo- treated normal controls. They were allowed free access to regular rat chow and studied 6 weeks after surgery. Liver mRNAs and protein mass or activities of the above factors were studied. RESULTS: Plasma cholesterol concentration was significantly increased in the CRF group (P < 0.001) and was modestly lowered (P < 0.05) by Epo therapy. However, microsomal cholesterol concentration and LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA as well as HMG-CoAR activity, and Ch-7 alpha-H and LDLR protein mass measurements were virtually identical in the three groups. Thus, hepatic LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA and protein measurements in rats with CRF were similar to those of the normal control group representing an inappropriate response to the associated hypercholesterolemia. Epo therapy led to partial amelioration of CRF- associated hypercholesterolaemia with no discernible effect on hepatic tissue expression of the above factors.      

Comparative PET studies of the kinetics and distribution of cocaine and cocaethylene in baboon brain.

Recent studies have suggested that cocaethylene, an active metabolite of cocaine found in blood and postmortem brain of individuals self-administering cocaine and alcohol, may play a role in the increased toxicity seen when coadministering these 2 drugs. We have used positron emission tomography (PET) and carbon-11 (t1/2:20.4 min) labeled cocaine and cocaethylene to compare the short-term kinetics of cocaine and cocaethylene in baboon brain. The regional uptake of [11C]cocaine cocaethylene in baboon brain. The regional uptake of [11C]cocaine ([11C]COC) and [11C]cocaethylene ([11C]CE), 5-8 mCi and 4-6 micrograms, in baboon brain (n = 7) were similar but clearance from whole brain (global, GL) and from striatum (SR), thalamus (TH), and cerebellum (CB) was slower for cocaethylene. Steady-state distribution volumes (DV) were not significantly different in the striatum but were greater for cocaethylene in the thalamus, cerebellum, and whole brain. Debenzoylation of cocaethylene proceeded at about one-third the rate of cocaine, as determined by in vitro incubation of labeled cocaethylene and labeled cocaine with baboon plasma and with purified horse butyryl-cholinesterase (EC 3.1.1.8). Even though the slower clearance of cocaethylene could lead to longer tissue exposures and potentially accentuated or different physiological effects relative to cocaine, the difference between the 2 drugs is not large. Thus it is more likely that the direct actions of cocaine and alcohol on some organs, rather than cocaethylene, account for this enhanced toxicity.     

Spatial low frequency pattern analysis in positron emission tomography: a study between normals and schizophrenics.

Using the two-dimensional Fourier transform and the brain's centroidal principal axis, a method is developed for the analysis of PET metabolic brain images without the use of predefined anatomic regions of interest. We applied the method to images from a group of 11 normal and 12 medicated schizophrenics tested under resting conditions and under a visual task. A cortical/subcortical spatial pattern was found to be significant in two directions; anterior/posterior and chiasmatic (left-anterior/right-posterior). The best individual clinical classification (Jackknife classification) occurred under visual task at two axial brain levels: at the basal ganglia with correct classification rates of 91% and 84%, while the cerebellum had rates of 82% and 92%. These high classification rates were obtained using only the four coefficients of the lowest spatial frequency. These results point to the generalized brain dysfunction of regional glucose metabolism in chronic medicated schizophrenics both at rest and at a visual image-tracking task.     

Decreased brain metabolism in neurologically intact healthy alcoholics.

OBJECTIVE: The extent to which cerebral dysfunction in alcoholics is related to the direct effects of alcohol in the brain rather than to indirect mechanisms and/or alcohol withdrawal remains unclear. The purpose of this study was to evaluate whether healthy alcoholics with no evidence of alcohol-associated complications showed changes in brain glucose metabolism. METHOD: Positron emission tomography and [18F]-fluorodeoxyglucose were used to measure regional brain metabolism. The study group consisted of 22 normal, healthy, right-handed volunteers and 22 neurologically intact, healthy, right-handed alcoholics tested 6 to 32 days after alcohol discontinuation. RESULTS: Alcoholics showed significantly lower whole brain metabolism than normal control subjects. Normalization of regional metabolic values to the whole brain metabolic rate revealed that the left parietal and right frontal cortices were the most affected regions. Although the whole brain metabolic rate was correlated with the amount of time since alcohol discontinuation, the "normalized" decreases in left parietal and right frontal glucose metabolism were not. CONCLUSIONS: These findings support the contribution of the direct effect of alcohol as well as alcohol withdrawal on the changes in regional brain metabolism seen in alcoholics. They also provide evidence of cerebral changes in neurologically intact healthy alcoholics.