Biomedical subjects

J L Eberling

Publications and source records attributed to J L Eberling.

At least 19 recordsLinked to original sources

PubMed1999

Dopamine transporter loss and clinical changes in MPTP-lesioned primates.

Single photon emission computed tomography (SPECT) and the dopamine (DA) transporter tracer, 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT), were used to determine DA transporter density in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-lesioned monkeys with varying degrees of parkinsonism. The clinical stage of parkinsonism corresponded to SPECT measures of striatal DA transporter density suggesting that more severe parkinsonism was associated with a greater degree of dopaminergic terminal degeneration. These findings are similar to those reported earlier using positron emission tomography (PET) and the DA metabolism tracer, 6-[18F]fluoro-L-m-tyrosine (FMT), indicating that both are good methods for evaluating nigrostriatal degeneration in MPTP primate models.

Animals↗

PubMed1999

Effects of subcortical cerebral infarction on cortical glucose metabolism and cognitive function.

BACKGROUND: The mechanism of dementia in subcortical cerebral infarction is incompletely understood. OBJECTIVE: To determine how cognitive function is related to cortical metabolism in patients with subcortical infarction and a continuum of cognitive impairment. METHODS: We used positron emission tomography (PET) and the glucose metabolic tracer fludeoxyglucose F 18 to study 8 patients with subcortical stroke and normal cognitive function (S-CN), 5 patients with subcortical stroke and cognitive impairment (S-CI) who did not have dementia, 8 patients with subcortical stroke and dementia (S-D), and 11 controls with no cognitive impairment or stroke. A subset of patients had absolute regional cerebral metabolic rate of glucose (CMRglc) determined, while in all subjects regional tracer uptake normalized to whole brain tracer uptake was calculated. PET data were analyzed by constructing volumes of interest using coregistered magnetic resonance imaging data and correcting the PET data for atrophy. RESULTS: Global CMRglc was significantly lower in the patients with S-D than in the control and S-CN groups, with S-CI rates intermediate to those of the S-D and S-CN groups. Absolute regional CMRs of glucose were similar in the S-D and S-CI groups and in the control and S-CN groups. The regional pattern, however, showed lower right frontal regional CMRglc ratios in all stroke groups compared with the controls. There were modest correlations between performance on the Mini-Mental State Examination and whole brain CMRglc when all 4 groups were included. CONCLUSIONS: These results demonstrate that subcortical infarction produces global cerebral hypometabolism, which is related to the clinical status of the patients. In addition, specific frontal lobe hypometabolism also appears to be a feature of subcortical infarction. Taken together, both global and regional effects on cortical function mediate the production of clinical symptoms in patients with subcortical strokes.

Aged↗

PubMed1998

A novel MPTP primate model of Parkinson's disease: neurochemical and clinical changes.

Positron emission tomography (PET) and the dopamine (DA) metabolism tracer, [18F]6-fluoro-L-m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and the clinical stage of parkinsonism monkeys following either unilateral ICA MPTP infusion or unilateral ICA MPTP infusion and subsequent varying sequential systemic doses of MPTP. Clinical stage corresponded to PET measures of striatal DA metabolism, showing the usefulness of the overlesioned hemiparkinsonian monkey as a stable model of various stages of Parkinson's disease (PD).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1998

An in vivo microdialysis study of striatal 6-[18F]fluoro-L-m-tyrosine metabolism.

In vivo brain microdialysis was used to monitor 6-[18F]fluoro-L-m-tyrosine (FMT) uptake and metabolism in the striatum of conscious freely moving rats for 3 hours after FMT injection (25 mg/kg, i.v.). Microdialysate collected 20 to 120 min post-dose, contained FMT at a concentration (0.2 to 0.3 nM) approximately ten-fold below that of its metabolite [18F]fluoro-3-hydroxyphenylacetic acid (FPAC; 3.2 to 3.3 nM). D-amphetamine (2.5 mg/kg, i.p.) injected 120 min after significantly increased microdialysate FPAC (3.27 +/- 0.31 nM to 4.51 +/- 0.45 nM) in control but not reserpinized rats. Taken together these data demonstrate FMT is heavily metabolized following its entry into the striatum yielding FPAC which appears to be stored, at least in part, in reserpine sensitive cytoplasmic vesicles. Presynaptic retention of FPAC may contribute to the preferential accumulation of FMT positron emission tomography (PET) signaling in dopaminergic brain areas.

Animals↗

PubMed1998

Brain perfusion imaging predicts survival in Alzheimer's disease.

BACKGROUND: The variability of disease course in patients diagnosed with AD makes prediction of survival difficult, despite the identification of numerous predictors to date. This study evaluated the predictive utility of measurements of regional cerebral blood flow (rCBF) obtained with SPECT in a group of AD patients. METHODS: Fifty AD patients were studied with SPECT and followed longitudinally. SPECT measures of relative rCBF were calculated by measuring radioactivity densities in dorsolateral frontal, orbitofrontal, temporal, and parietal cortex normalized to occipital cortical radioactivity density. Subjects were classified into three tertiles of rCBF ratios for each region. These rCBF ratios were used as predictors of survival in life-table and proportional hazard models to predict survival. RESULTS: Right parietal rCBF was a significant predictor of survival in the life-table analysis, with subjects in the lowest tertile having shortest survivals. No other brain region was a significant predictor of survival. In a proportional hazards model when a variety of other potential predictors were accounted for, right parietal rCBF ratio remained a significant predictor. CONCLUSIONS: These results demonstrate that brain perfusion in the right parietal lobe is a significant predictor of survival in patients with AD even when other predictors are taken into consideration. This suggests that SPECT perfusion imaging may provide additional useful information on disease prognosis in AD.

Aged↗

PubMed1997

Clinical studies of cerebral blood flow in Alzheimer's disease.

Studies of Alzheimer's disease using single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have found reductions in blood flow and glucose metabolism in temporal and parietal cortex. In 50 AD patients who underwent neuropsychological testing and SPECT perfusion imaging, we found significant correlations between perfusion and performance on the Mini-Mental Status Examination in the frontal and parietal lobes. In addition, specific correlations between perfusion in the frontal lobes and performance on tests of frontal lobe ability were noted. These findings, while suggesting the importance of perfusion measures in determining clinical features of the disease, do not clearly define perfusion changes as primary, since similar findings have been seen when metabolism is studied. In a separate group of 5 AD patients and 16 controls, we used PET with the perfusion tracer HIPDM and examined cerebrovascular reactivity to carbon dioxide inhalation. We found that in multiple brain regions, including the temporal lobes, AD patients showed robust and significant increases in perfusion in response to carbon dioxide that did not differ from the response seen in the controls. Taken together, these results show that while perfusion changes are important in AD, they are not clearly either primary or limiting.

Alzheimer Disease↗

PubMed1997

PET studies of functional compensation in a primate model of Parkinson's disease.

MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a neurotoxin that produces degeneration of nigrostriatal dopaminergic neurons and a chronic parkinsonian condition in primates. Positron emission tomography (PET) studies of rhesus macaques at various time points following unilateral MPTP administration demonstrated a different time course of degeneration in the dopaminergic terminals in the putamen and in the cell bodies in the substantia nigra, consistent with other evidence of retrograde degeneration. In addition, the substantia nigra showed a transient upregulation in dopaminergic function in the lesioned hemisphere indicating functional compensation. This plasticity has important implications for the therapeutic effects of growth factors and other potential treatments for neurodegenerative diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1997

6-[18F]fluoro-L-m-tyrosine: metabolism, positron emission tomography kinetics, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesions in primates.

The tracer 6-[18F]fluoro-L-m-tyrosine (FMT) was studied with regard to its biochemistry and kinetics, as well as its utility in evaluating brain dopaminergic function in primates before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment using positron emission tomography (PET). Plasma analysis of FMT and its F18-labeled metabolites 6-fluoro-3-hydroxyphenylacetic acid (FPAC) and 6-fluoro-3-hydroxyphenylethylamine (FMA) during PET scanning enabled kinetic analysis of FMT uptake. A separate study examined brain FMT metabolism in MPTP-naive monkeys euthanized 60 or 120 min after FMT injection. Almost 60% of total plasma F-18 activity was associated with FPAC and FMA 120 min after FMT injection. The FMT signal accumulated preferentially in dopaminergic areas such as caudate and putamen. This bilateral FMT signal was disrupted after unilateral intracarotid artery (ICA) MPTP infusion which reduced ipsilateral striatal activity. A three compartment three kinetic rate constant model for FMT uptake revealed reduced FMT decarboxylation (k3) in ipsilateral caudate and putamen after unilateral MPTP although a further decrease was not evident after intravenous MPTP. FPAC was the major F-18 species in all brain regions except in cerebellum where FMT was predominant 60 min post-mortem. FPAC was most concentrated in dopaminergic areas whereas lower levels occurred in areas containing few dopamine terminals. These data demonstrate preferential FMT metabolism and F-18 retention in dopaminergic tissue and support the use of FMT to evaluate normal and abnormal dopaminergic function.

Animals↗

PubMed1997

A methodology for specifying PET VOI's using multimodality techniques.

Volume-of-interest (VOI) extraction for radionuclide and anatomical measurements requires correct identification and delineation of the anatomical feature being studied. We have developed a toolset for specifying three-dimensional (3-D) VOI's on a multislice positron emission tomography (PET) dataset. The software is particularly suited for specifying cerebral cortex VOI's which represent a particular gyrus or deep brain structure. A registered 3-D magnetic resonance image (MRI) dataset is used to provide high-resolution anatomical information, both as oblique two-dimensional (2-D) sections and as volume renderings of a segmented cortical surface. VOI's are specified indirectly in two dimensions by drawing a stack of 2-D regions on the MRI data. The regions are tiled together to form closed triangular mesh surface models, which are subsequently transformed into the observation space of the PET scanner. Quantification by this method allows calculation of radionuclide activity in the VOI's, as well as their statistical uncertainties and correlations. The methodology for this type of analysis and validation results are presented.

Brain↗

PubMed1996

Functional imaging predicts cognitive decline in Alzheimer's disease.

Eighteen patients with Alzheimer's disease were studied with positron emission tomographic measurements of regional cerebral metabolism of glucose. All patients were initially diagnosed and evaluated, underwent positron emission tomography, and then were followed with annual reevaluations, at which time the Mini-Mental State Examination (MMSE) was performed. Patients were followed for an average of 2.5 years, and the rate of cognitive decline was calculated by determining the rate of change in the MMSE score defined as the MMSE score at the initial evaluation minus the MMSE score at the last examination, divided by the number of months between testing. The regional cerebral metabolic rates for glucose determined at the time of the first MMSE were then regressed on these changes in scores. Results showed that glucose metabolic rates in posterior temporal and primary visual cortex regions were significantly correlated with the subsequent rate of cognitive deterioration. These associations were not confounded by age, length of follow-up, baseline MMSE score, or education. Stratification on gender suggested that these associations were much stronger in women than in men. These results replicate previous findings showing that functional brain imaging is predictive of the rate of cognitive decline in Alzheimer's disease.

Age Factors↗

PubMed1996

Iodine-123-5-iodo-6-nitroquipazine: SPECT radiotracer to image the serotonin transporter.

UNLABELLED: Because serotonergic function has been implicated in the pathophysiology of a number of diseases of the nervous system, efforts to image this system in vivo have received considerable recent attention. Promising preliminary results with the tracer 5-iodo-6-nitroquipazine (INQUIP) have prompted us to perform further studies designed to validate the use of the tracer as an in vivo ligand for the serotonin transporter. METHODS: We studied six adult macaca mulatta in eight experiments which involved SPECT imaging at 17 to 24 hr post-tracer injection, including three experiments with coinjection of the 123I-and 125I-radiolabeled tracer for direct comparison of autoradiography and SPECT, and three experiments in which animals were lesioned with the serotonergic neurotoxin (+/-)3,4-methyl-enedioxymethamphetamine (MDMA). In addition, we evaluated the metabolism of the tracer in the brain and periphery. RESULTS: SPECT images obtained at 17 and 24 hr reflected the known pattern of distribution of serotonin transporters and also showed close correspondence to the autoradiograms. Ratios of binding in the brain-stem to binding in the cerebellum were close to 3 at 17 hr. autoradiograms from an MDMA-treated animal showed up to 95% reductions of binding, while the SPECT data showed smaller reductions. Virtually all of the tracer in the brain stem was in the form of unmetabolized parent compound, but plasma showed rapid peripheral metabolism of the tracer. CONCLUSION: These results demonstrate that INQUIP SPECT images are sensitive measures of in vivo binding to the serotonin transporter, and support the further development of the tracer as a method for the in vivo study of serotonergic neurons in humans.

Animals↗

PubMed1995

Temporal lobe perfusion on single photon emission computed tomography predicts the rate of cognitive decline in Alzheimer's disease.

OBJECTIVE: To examine the ability of relative regional cerebral blood flow as measured by single photon emission computed tomography to predict longitudinal course of cognitive decline in Alzheimer's disease. DESIGN: Single photon emission computed tomography using the blood flow tracer 123I-N-isopropyl-p-iodoamphetamine was performed at initial evaluation and was used to predict the rate of cognitive decline over a follow-up period from 1 to 4 years. SETTING: Outpatient university dementia clinic and center for functional imaging. PARTICIPANTS: Twenty-nine patients met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probably or possible AD. RESULTS: Temporal lobe regional cerebral blood flow ratio at initial evaluation correlated with rate of decline in Mini-Mental State Examination over the longitudinal follow-up. Temporal regional cerebral blood flow ratio also predicted rate of decline of specific memory measures on the California Verbal Learning Test. Neither parietal nor frontal ratios predicted rate of cognitive decline. Dorsolateral frontal hypoperfusion was associated with the emergence of perseverative behaviors over time. Age, prior dementia duration, estimated prior rate of decline, and initial severity did not predict rate of cognitive decline. CONCLUSION: Results suggest that regional perfusion on single photon emission computed tomography may predict cognitive decline in Alzheimer's disease better than these demographic and course variables.

Aged↗

PubMed1995

Reduced temporal lobe glucose metabolism in aging.

The results of a positron emission tomography study of regional cerebral metabolic rates of glucose are reported for 8 healthy old subjects (mean age, 66 yr; standard deviation [SD], 5) and 9 young subjects (mean age, 27 yr; SD, 4.6) using a high-resolution positron emission tomograph and the glucose metabolic tracer 18F-fluorodeoxyglucose. Older subjects showed significantly lower cerebral metabolic rates than did the young subjects, in anterior, middle, and posterior temporal neocortex and in mesial temporal cortex, with the largest differences occurring in anterior temporal cortex (temporal pole). The current findings may reflect either decreases in regional cerebral metabolic rates for glucose that occur with normal aging, or early indications of cognitive dysfunction that is associated with age-related disorders.

Adult↗

PubMed1993

The cortical topography of temporal lobe hypometabolism in early Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a pathological process with specific predilection for association neocortex and the mesial temporal lobes. Recently developed high-resolution positron emission tomographs (PET) are able to quantitate regional cerebral metabolic rates for glucose (rCMRglc) in these brain regions and map the distribution of the metabolic consequences of Alzheimer pathology. In order to evaluate the relative involvement of mesial and neocortical temporal lobe brain regions in AD, we studied 22 AD patients, 11 of whom were mildly demented and 11 of whom were moderately demented in comparison to 8 age-matched control subjects. We used a PET instrument with 2.6 mm in-plane resolution and quantitated rCMRglc in anterior, middle, and posterior temporal neocortex, visual association cortex, primary visual cortex, and mesial temporal cortex. Although the moderately demented AD patients showed significantly lower metabolic rates than controls in visual association cortex and all temporal lobe regions except right anterior temporal neocortex, the mildly demented patients were different from the controls in only middle temporal neocortex. Considerable variability was found in the relative involvement of mesial temporal lobes and temporal neocortex in the AD patients, however, as shown by greater variance of a ratio of mesial temporal lobe rCMRglc to temporal neocortical rCMRglc (MES/NEO ratio) in the AD patients than the controls. A series of stepwise multiple regressions showed that this ratio was related to patient cognitive symptomatology, with more severely memory-impaired patients showing lower MES/NEO ratios, while patients with visuospatial disturbances showed higher MES/NEO ratios. In addition, the only biological variable that was related to this ratio was patient age, with older patients showing lower MES/NEO ratios. These results indicate that mesial temporal lobe structures are not invariably the earliest nor the most severely metabolically involved brain regions in AD and that the relative involvement of the mesial and neocortical temporal lobe is related to the patient's cognitive symptoms and age.

Aged↗

PubMed1993

In vivo imaging of the 5-hydroxytryptamine reuptake site in primate brain using single photon emission computed tomography and [123I]5-iodo-6-nitroquipazine.

Previous experiments have demonstrated that 5-iodo-6-nitro-2-piperazinylquinoline (5-I-6-NQP) is a potent and selective ligand for studying brain 5-hydroxytryptamine (5-HT) reuptake sites. We performed in vivo imaging in non-human primates using single photon emission computed tomography (SPECT) and the 123I-labeled compound [123I]5-I-6-NQP. These studies showed rapid brain uptake, with slow egress of the tracer from the brainstem, a region rich in 5-HT reuptake sites. Loss of the tracer from regions with a lower density of these sites, such as cerebellum, was relatively more rapid. Pretreatment of animals with paroxetine increased the washout of tracer from the brainstem to rates similar to that seen in cerebellum. Brainstem to cerebellar ratios of tracer accumulation were > 2 by 8 h after injection, and in paroxetine pretreated animals remained close to 1. These results indicate that the radiotracer has characteristics suitable for use as a SPECT imaging agent of serotonin reuptake sites.

Animals↗

PubMed1993

Cognitive correlates of regional cerebral blood flow in Alzheimer's disease.

OBJECTIVE: To study the relationship between relative regional cerebral blood flow (rCBF) and performance on a variety of neuropsychological tests in a group of subjects with Alzheimer's disease. DESIGN: Analysis of the relationship between relative rCBF and neuropsychological performance using stepwise multiple regressions and Pearson Product-Moment Correlation coefficients. SETTING: University dementia clinic and research laboratory. PARTICIPANTS: Twelve mildly demented patients with Alzheimer's disease (Mini-Mental State examination [MMSE] scores, 24 to 29; age, 56 to 78 years); 38 moderately demented patients with Alzheimer's disease (MMSE scores, 0 to 23; age, 59 to 86 years); and eight normal control subjects (MMSE scores, 27 to 30; age, 61 to 79 years). MAIN OUTCOME MEASURES: Single photon emission computed tomography and the blood flow tracer N-isopropyl-p-iodoamphetamine iodine 123 were used to measure relative rCBF. Cognitive performance was assessed by grouping neuropsychological tests into clusters reflecting frontal lobe abilities, perseveration, memory, and visuoconstructive abilities. RESULTS: While MMSE score was a significant (P < .05) predictor of visuoconstruction, frontal lobe, and memory cluster scores, relative rCBF was a weaker predictor of neuropsychological performance, with only right orbitofrontal relative rCBF emerging as a significant (P < .05) predictor of the frontal cluster score and right parietal relative rCBF as a significant (P < .05) predictor of the visuoconstruction cluster score. CONCLUSIONS: These results support our a priori grouping of neuropsychological tests into frontal and visuoconstruction clusters and suggest that these two clusters are good measures of frontal and parietal lobe function, respectively.

Aged↗

PubMed1992

Cognitive function and regional cerebral blood flow in Parkinson's disease.

In order to investigate relationships between cognition and regional brain function, we studied 20 non-demented patients with idiopathic Parkinson's disease (PD), 21 mildly demented patients with Alzheimer's disease (AD) and 24 control subjects using cognitive testing and single photon emission computerized tomographic (SPECT) measurements of relative regional cerebral blood flow (rCBF). Neuropsychological tests were grouped into clusters reflecting frontal lobe executive abilities, perseveration, memory and visuospatial ability, with a summary score summarizing performance in all four of these spheres. SPECT imaging utilized the tracer [123I]N-isopropyl-p-iodoamphetamine with a relative measure of regional tracer uptake normalized to occipital radiotracer uptake (rCBF ratios). Patients with PD performed more poorly than controls in all cognitive domains, and were intermediate to AD patients and controls in tests of memory and overall cognitive functioning. Those PD patients who performed most poorly on neuropsychological testing showed lowest rCBF ratios in left and right temporal lobes. Using a stepwise multiple regression procedure, we examined patterns of correlations between cognitive clusters and predictor variables, including rCBF ratios, in the PD patients. We found that while patient age was a strong determinant of performance on the memory cluster and the summary score, dorsolateral frontal lobe perfusion and scores on a depression inventory accounted for a greater proportion of the variance of the frontal lobe and perseveration clusters than did age. These results imply that different neural mechanisms are responsible for the different aspects of cognitive decline seen in PD patients, with overall cognitive function closely related to age and temporal perfusion, while frontal lobe abilities are more linked to frontal perfusion and the presence of depression.

Aged↗

PubMed1991

MRI, CT, SPECT, PET: their use in diagnosing dementia.

The differential diagnosis of the dementia syndrome may pose a difficult clinical problem, since the most common dementia, Alzheimer's disease (AD), is marked by normal laboratory tests. Neuroimaging has played an important role in evaluating the demented patient, and its uses are growing. Computed tomography (CT) is useful for excluding reversible and treatable causes of dementia, such as subdural hematoma and tumor. More recently, magnetic resonance imaging (MRI) has improved our ability to diagnose vascular disease and may show the presence of cerebral infarcts and white matter disease not visible on CT. Single photon emission computed tomography (SPECT) and positron emission tomography (PET), techniques that visualize such cerebral functions as glucose metabolism and blood flow, may provide positive evidence supportive of the diagnosis of AD.

Alzheimer Disease↗