Biomedical subjects

Thomas Chaly

Publications and source records attributed to Thomas Chaly.

9 recordsLinked to original sources

PubMed2004

Caudate nucleus: influence of dopaminergic input on sequence learning and brain activation in Parkinsonism.

In this study, we tested the hypotheses that (1) the acquisition of sequential information is related to the integrity of dopaminergic input to the caudate nucleus; and (2) the integrity of dopaminergic input to the caudate nucleus correlates significantly with brain activation during sequence acquisition. Twelve early stage Parkinson's disease (PD) patients and six age-matched healthy volunteers were scanned using a dual tracer PET imaging design. All subjects were scanned with [(18)F]fluoropropyl-betaCIT (FPCIT) to measure striatal dopamine transporter (DAT) binding and with [(15)O]water to assess activation during a sequence learning task where movements were made to a repeating sequence of eight targets. Caudate and putamen DAT binding in the PD cohort was reduced by 15% and 43%, respectively. In PD, caudate DAT binding correlated with target acquisition (R = 0.57, P < 0.05), while putamen DAT binding did not correlate with performance. In volunteers, caudate DAT binding correlated with learning-related activation (P < 0.05, corrected for multiple comparisons) in the left dorsolateral and ventral prefrontal cortices, the anterior cingulate and premotor regions, and the right cerebellum. A significant correlation with caudate DAT binding was additionally detected in the right anteromedial thalamus, extending into the rostral midbrain. By contrast, in the PD cohort, most of these regional relationships were lost: Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic tone. Our findings suggest that sequence learning is normally associated with tight coupling between dopaminergic input to the caudate and thalamo-cortical functional activity. Despite minimal reductions in nigro-caudate input, PD patients demonstrate a loss of this coupling early in the disease.

Aged↗

PubMed2004

Radiosynthesis of [18F] N-(3-Fluoropropyl)-2-beta-Carbomethoxy-3-beta-(4-Bromophenyl) Nortropane and the regional brain uptake in non human primate using PET.

A synthetic procedure for the preparation of [18F]FPCBT, an imaging agent for the dopamine transporter (DAT), has been developed. The radiosynthesis was carried out in a two step procedure. Even though the yield was low, we were able to prepare 20 to 30 mCi of the product, which was enough for two or three studies. The radiochemical purity was greater than 96%. The in vivo properties of this radiotracer were evaluated using baboon and it showed highest uptake in the striatum. The studies also revealed that the maximum uptake was reached within 7 to 10 minutes post injection. Plasma metabolite analysis indicated that there is only one metabolite and it is less lipophilic than the parent compound. [18F]FPCBT displayed good brain uptake and its high target to non target ratio indicate that it is a potential candidate for DAT imaging.

Animals↗

PubMed2004

Gene microarray analysis of human brain arteriovenous malformations.

OBJECTIVE: Human brain arteriovenous malformations (BAVMs) display abnormal expression of various angiogenesis-related genes and their products. We examined gene expression patterns in BAVMs by the gene microarray technique. METHODS: We analyzed BAVM and control brain samples obtained by temporal lobectomy for medically intractable seizure by Affymetrix Human Gene Set U95Av2 (Affymetrix, Inc., Santa Clara, CA). The gene microarray data were compared with new and previously published data that used conventional molecular biology techniques. RESULTS: We analyzed six BAVM and five control brain samples. From 12,625 gene probes assayed, 1781 gene probes showed differential expression between BAVMs and controls. BAVM samples had a gene expression pattern that was distinct from those of control brain samples. Increased messenger ribonucleic acid expression of vascular endothelial growth factor A was accompanied by increased expression of its protein product. A majority of the gene data was in agreement with previously published data. The gene microarray data generated a new testable hypothesis regarding integrin, and we found increased expression of integrin alphavbeta3 protein in BAVMs. CONCLUSION: The gene expression pattern of BAVMs was distinct from those of control brain samples. We verified the gene microarray data by demonstrating that increased gene expression levels for angiogenesis-related molecules were accompanied by increased levels of their protein product expression. The gene microarray technique may be a useful tool to study multiple pathways simultaneously in BAVM specimens.

Adolescent↗

PubMed2003

Induction of focal angiogenesis through adenoviral vector mediated vascular endothelial cell growth factor gene transfer in the mature mouse brain.

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and morphogen, which stimulates angiogenesis in a wide variety of tissues and lesions in vivo. In this study, we applied adenoviral vector delivered human VEGF165 cDNA to develop focal non-tumor angiogenesis in the mature mouse brain. Seventy-two adult CD-1 mice underwent Ad h VEGF, Ad lacZ, and saline injection for up to fourweeks. An adenoviral suspension containing 1 x 10(9) particles was injected stereotactically into the right hemisphere of the brain. The results showed that VEGF expression was increased in the Ad h VEGF transduced mice compared to Ad lacZ or saline injected mice ( P < 0.05). VEGF-positive cells were mainly located in the injection hemisphere of Ad h VEGF transduced mice. Quantitative vessel counting showed that microvessels in the Ad h VEGF transduced mice increased following 2 weeks of Ad h VEGF gene transfer compared to the other two groups (Ad h VEGF:241 +/- 19 vs. Ad lacZ :148 +/- 17 and Saline:150 +/- 14 vessels/mm2, P < 0.05). Morphology showed typical angiogenic changes. PCNA-positive staining confirmed these microvessels were actively proliferating. Our study demonstrates that Ad h VEGF-induced VEGF hyper-stimulation causes focal angiogenesis in the mature mouse brain. This novel method of inducing in vivo brain focal angiogenesis provides an opportunity to study the molecular mechanisms independent of the confounding effects of upstream inciting stimuli such as ischemia or tumor.

Adenoviridae↗

PubMed2003

Dosimetry of the dopamine transporter radioligand 18F-FPCIT in human subjects.

UNLABELLED: This study was designed to evaluate the radiation dosimetry in human subjects for a new radiopharmaceutical, N-(3-(18)F-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane ((18)F-FPCIT). The goal was to determine a limiting dose consistent with accepted guidelines for use in clinical studies and to compare the radiation burden with other agents such as (123)I-FPCIT, (18)F-fluorodopa, and (18)F-FDG. METHODS: Dynamic PET scans of the urinary bladder were obtained in 6 subjects; 2 subjects had brain scans and 5 subjects had scans of the thorax or abdomen. Regions of interest were placed over composite images of each organ for which activity was visualized to generate time-activity curves. Doses were calculated from residence times using the MIRDOSE3 program. RESULTS: The critical organ for dosimetry is the urinary bladder wall with a dose of 0.0586 +/- 0.0164 mGy/MBq. The dose comes primarily (97.2%) from activity in the urinary bladder contents. The dose is lower than any of the other agents used commonly in PET to assess dopaminergic function. The effective dose equivalent (0.0120 mGy/MBq) is also lower than comparable compounds. CONCLUSION: (18)F-FPCIT has favorable dosimetry when compared with other agents used to study dopaminergic function. Doses as high as 853 MBq (23 mCi) may be given to adult patients and remain within accepted guidelines.

Adult↗

PubMed2002

Serotonin modulation of cerebral glucose metabolism measured with positron emission tomography (PET) in human subjects.

To develop a method to measure the dynamic response of the serotonin system in vivo, the effects of intravenously administered citalopram (the most selective of the serotonin reuptake inhibitors) on cerebral glucose metabolism were evaluated. Cerebral glucose metabolism was measured with positron emission tomography (PET) in 14 normal subjects scanned after administration of saline placebo and citalopram administered on 2 separate days. Citalopram administration resulted in a decrease in metabolism in the right anterior cingulate gyrus (BA 24/32), right superior (BA 9) and right middle frontal gyrus (BA 6), right parietal cortex (precuneus), right superior occipital gyrus, left thalamus, and right cerebellum. Increased metabolism was observed in the left superior temporal gyrus and left occipital cortex. Alterations in metabolism by acute citalopram administration involved the heteromodal association cortices that also show metabolic alterations in patients with geriatric depression and overlap with the regions affected by antidepressant treatment. Future studies will evaluate how the acute metabolic response to citalopram relates to the metabolic response after chronic treatment in patients with geriatric depression.

Adult↗

PubMed2002

Comparative analysis of striatal FDOPA uptake in Parkinson's disease: ratio method versus graphical approach.

UNLABELLED: Striatal-to-occipital ratio (SOR) and influx constant K(i)(occ) are commonly used as analytic parameters in L-3,4-dihydroxy-6-(18)F-fluorophenylalanine (FDOPA) PET studies. Both have been shown to be useful in discriminating Parkinson's disease (PD) patients from healthy subjects. We evaluated the relative performance of SOR and influx constant (K(i)(occ)) in the clinical assessment of nigrostriatal dopaminergic function in PD. METHODS: Twenty-one parkinsonian patients (Hoehn and Yahr scale I-IV; mean age +/- SD, 56 +/- 9.2 y) and 11 healthy subjects (mean age, 60 +/- 16 y) underwent 3-dimensional dynamic FDOPA scanning from 0 to 100 min. After spatial realignment, PET images at each frame were integrated by summing 4 central striatal slices, and time-activity curves (TACs) were generated after placing a standard set of elliptic regions of interest over striatal and occipital structures. SOR and K(i)(occ) values for each subject were then computed from TACs at different times using an input function from the occipital cortex. RESULTS: Both SOR and K(i)(occ) showed significant bilateral decreases in striatal dopamine uptake in the PD group compared with the control group. SOR values estimated for 10-min frames between 65 and 95 min are statistically equivalent in group discrimination. In addition, SOR values in the caudate and putamen correlated strongly with K(i)(occ), especially toward the end of the scanning epoch. Both parameters correlated significantly and comparably with Unified Parkinson's Disease Rating Scale motor scores. CONCLUSION: These results suggest that SOR determined from a single 10-min scan at 95 min is as accurate as K(i)(occ) in separating PD patients from healthy subjects and in predicting clinical measures of disease severity.

Case-Control Studies↗

PubMed1998

Quantitative Brain PET. Comparison of 2D and 3D Acquisitions on the GE Advance Scanner.

PURPOSE: Recent developments in the design of positron emission tomography (PET) scanners have made three-dimensional (3D) data acquisition attractive because of significantly higher sensitivity compared to the conventional 2D mode (with lead/tungsten septa extended). However, the increased count rate in 3D mode comes at the cost of increased scatter, randoms, and dead time. Several schemes to correct for these effects have been proposed and validated in phantom studies. In this study, we evaluated the overall improvement afforded by 3D imaging in quantitative human brain PET studies carried out at our institution.METHODS: Subjects were studied using sequential/interleaved 2D and 3D data acquisition with a GE Advance scanner. We calculated regional and global cerebral glucose metabolism with [(18)F]flourodeoxyglucose (FDG) and estimated rate constants for striatal [(18)F]fluorodopa (FDOPA) uptake.RESULTS: FDG: Global mean glucose metabolic rates were in almost complete agreement (within 1%) between the two modes whereas the regional differences ranged from -7.7% to +9% for all cortical structures. However, for small regions (<2 cm(2)) like caudate nuclei, the maximum difference was 14.7%. FDOPA: A significant improvement in image quality was evident in 3D mode and there was complete agreement between the estimated parameters in the two scanning modes for the same noise equivalent counts: Striatal-to-occipital ratio (SOR) and striatal FDOPA uptake (K(i)(FD)) had mean differences of less than 2% and 5%, respectively.CONCLUSIONS: 3D FDG studies can be done with either half the injected dose or half the scan duration to a comparable 2D study. 3D PET imaging has distinct advantages over 2D in the quantitative fluorodopa studies.

Journal Article↗

PubMedDate not supplied

Acute and chronic effects of citalopram on cerebral glucose metabolism in geriatric depression.

OBJECTIVE: In vivo studies of serotonin function have been limited by the lack of safe and selective pharmacologic agents and availability of suitable radiotracers. In the present study, the authors evaluated the cerebral metabolic effects of acute and continued administration of the selective serotonin reuptake inhibitor citalopram in patients with geriatric depression as a potential marker of serotonin dysfunction. METHODS: Six patients with geriatric depression and five comparison subjects underwent two resting positron emission tomography (PET) studies, performed after administration of a placebo infusion (Day 1) and a citalopram infusion (40 mg, Day 2). The patients were re-scanned after 8 weeks of treatment with the oral medication. RESULTS: The elderly comparison subjects demonstrated greater right-hemisphere cortical decreases than the patients. The depressed patients demonstrated greater left-hemisphere cortical decreases than comparison subjects. The depressed patients demonstrated greater increases in the right putamen and left occipital cortex. After 8 weeks of citalopram treatment, regional decreases and increases in metabolism were observed. CONCLUSION: These findings suggest regional deficits and also compensatory responses in the acute metabolic response to citalopram in the patients. These preliminary results suggest that the cerebral metabolic response to citalopram may be a useful marker of the pathophysiology of serotonin function in geriatric depression.

Aged↗