[Show abstract][Hide abstract] ABSTRACT: Objective:
Late-life depression (LLD) has a substantial public health impact and is both a risk factor for and a prodrome of dementia. Positron emission tomography (PET) studies of cerebral glucose metabolism have demonstrated sensitivity in evaluating neural circuitry involved in depression, aging, incipient cognitive decline, and dementia. The present study evaluated the long term effects of a course of antidepressant treatment on glucose metabolism in LLD patients.
Nine LLD patients and seven non-depressed control subjects underwent clinical and cognitive evaluations as well as brain magnetic resonance imaging and PET studies of cerebral glucose metabolism at baseline, after 8 weeks of treatment with citalopram for a major depressive episode (patients only), and at an approximately 2-year follow-up.
The majority of LLD patients were remitted at follow-up (7/9). Neither patients nor controls showed significant cognitive decline. The patients showed greater increases in glucose metabolism than the controls in regions associated with mood symptoms (anterior cingulate and insula). Both groups showed decreases in metabolism in posterior association cortices implicated in dementia.
Longitudinal changes in cerebral glucose metabolism are observed in controls and in LLD patients without significant cognitive decline that are more extensive than the decreases in brain volume. Longer duration follow-up studies and the integration of other molecular imaging methods will have implications for understanding the clinical and neurobiological significance of these metabolic changes.
Full-text · Article · Apr 2013 · International Journal of Geriatric Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Variability in the affective and cognitive symptom response to antidepressant treatment has been observed in geriatric depression. The underlying neural circuitry is poorly understood. This study evaluated the cerebral glucose metabolic effects of citalopram treatment and applied multivariate, functional connectivity analyses to identify brain networks associated with improvements in affective symptoms and cognitive function. Sixteen geriatric depressed patients underwent resting positron emission tomography (PET) studies of cerebral glucose metabolism and assessment of affective symptoms and cognitive function before and after 8 weeks of selective serotonin reuptake inhibitor treatment (citalopram). Voxel-wise analyses of the normalized glucose metabolic data showed decreased cerebral metabolism during citalopram treatment in the anterior cingulate gyrus, middle temporal gyrus, precuneus, amygdala, and parahippocampal gyrus. Increased metabolism was observed in the putamen, occipital cortex, and cerebellum. Functional connectivity analyses revealed two networks which were uniquely associated with improvement of affective symptoms and cognitive function during treatment. A subcortical-limbic-frontal network was associated with improvement in affect (depression and anxiety), while a medial temporal-parietal-frontal network was associated with improvement in cognition (immediate verbal learning/memory and verbal fluency). The regions that comprise the cognitive network overlap with the regions that are affected in Alzheimer's dementia. Thus, alterations in specific brain networks associated with improvement of affective symptoms and cognitive function are observed during citalopram treatment in geriatric depression.
Full-text · Article · Oct 2011 · Human Brain Mapping
[Show abstract][Hide abstract] ABSTRACT: Given the challenges in the clinical management of geriatric depression, research over the past decade has focused on developing early neurobiological markers of antidepressant treatment response. This study tested the hypothesis that lower baseline glucose metabolism and greater acute cerebral metabolic responses to a single, intravenous (IV) dose of the selective serotonin reuptake inhibitor (SSRI) citalopram would be associated with greater improvement of depressive symptoms after 12 weeks of citalopram treatment in geriatric depression.
sixteen geriatric depressed patients underwent two scans to measure cerebral glucose metabolism after administration of either a saline placebo or citalopram infusion (40 mg, IV). Then, the patients were treated with the oral citalopram medication for 12 weeks.
greater improvement of depressive symptoms was associated with lower baseline metabolism in anterior cingulate, superior, middle, and inferior frontal gyri (bilaterally), inferior parietal lobule (bilaterally), precuneus (right), insula (left), parahippocampal gyrus (right), caudate (bilaterally), and putamen (left) regions. Greater improvement of depressive symptoms was associated with greater reductions in metabolism after acute citalopram administration in similar brain regions, including additional posterior cortical regions.
lower baseline cerebral metabolism and greater decreases with acute citalopram administration are associated with better antidepressant response to chronic citalopram treatment. These data are consistent with previous studies of total sleep deprivation and suggest that dynamic, early adaptive changes or normalization of cerebral metabolism may represent early neurobiological markers of chronic SSRI treatment response in geriatric depression.
Preview · Article · Jan 2011 · The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Objectives: Given the challenges in the clinical management of geriatric depression, research over the past decade has focused on developing early neurobiological markers of antidepressant treatment response. This study tested the hypothesis that lower baseline glucose metabolism and greater acute cerebral metabolic responses to a single, intravenous (IV) dose of the selective serotonin reuptake inhibitor (SSRI) citalopram would be associated with greater improvement of depressive symptoms after 12 weeks of citalopram treatment in geriatric depression.
Methods: Sixteen geriatric depressed patients underwent two scans to measure cerebral glucose metabolism after administration of either a saline placebo or citalopram infusion (40 mg, IV). Then, the patients were treated with the oral citalopram medication for 12 weeks.
Results: Greater improvement of depressive symptoms was associated with lower baseline metabolism in anterior cingulate, superior, middle, and inferior frontal gyri (bilaterally), inferior parietal lobule (bilaterally), precuneus (right), insula (left), parahippocampal gyrus (right), caudate (bilaterally), and putamen (left) regions. Greater improvement of depressive symptoms was associated with greater reductions in metabolism after acute citalopram administration in similar brain regions, including additional posterior cortical regions.
Conclusions: Lower baseline cerebral metabolism and greater decreases with acute citalopram administration are associated with better antidepressant response to chronic citalopram treatment. These data are consistent with previous studies of total sleep deprivation and suggest that dynamic, early adaptive changes or normalization of cerebral metabolism may represent early neurobiological markers of chronic SSRI treatment response in geriatric depression.
No preview · Article · Dec 2010 · American Journal of Geriatric Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Positron Emission Tomography (PET) studies of cerebral glucose metabolism have demonstrated sensitivity in evaluating the functional neuroanatomy of treatment response variability in depression, as well as in the early detection of functional changes associated with incipient cognitive decline. The evaluation of cerebral glucose metabolism in late life depression may have implications for understanding treatment response variability, as well as evaluating the neurobiological basis of depression in late life as a risk factor for dementia.
Sixteen patients with geriatric depression and 13 comparison subjects underwent resting PET studies of cerebral glucose metabolism, as well as magnetic resonance (MR) imaging scans to evaluate brain structure.
Cerebral glucose metabolism was elevated in geriatric depressed patients relative to comparison subjects in anterior (right and left superior frontal gyrus) and posterior (precuneus, inferior parietal lobule) cortical regions. Cerebral atrophy (increased cerebrospinal fluid [CSF] and decreased grey and white matter volumes) were observed in some of these regions, as well. Regional cerebral metabolism was positively correlated with severity of depression and anxiety symptoms.
In contrast to decreased metabolism observed in normal aging and neurodegenerative conditions such as Alzheimer's disease, cortical glucose metabolism was increased in geriatric depressed patients relative to demographically matched controls, particularly in brain regions in which cerebral atrophy was observed, which may represent a compensatory response.
Full-text · Article · Aug 2009 · International Journal of Geriatric Psychiatry
[Show abstract][Hide abstract] ABSTRACT: To determine whether changes in D(2) receptor availability are present in carriers of genetic mutations for primary dystonia.
Manifesting and nonmanifesting carriers of the DYT1 and DYT6 dystonia mutations were scanned with [(11)C] raclopride (RAC) and PET. Measures of D(2) receptor availability in the caudate nucleus and putamen were determined using an automated region-of-interest approach. Values from mutation carriers and healthy controls were compared using analysis of variance to assess the effects of genotype and phenotype. Additionally, voxel-based whole brain searches were conducted to detect group differences in extrastriatal regions.
Significant reductions in caudate and putamen D(2) receptor availability were evident in both groups of mutation carriers relative to healthy controls (p < 0.001). The changes were greater in DYT6 relative to DYT1 carriers (-38.0 +/- 3.0% vs -15.0 +/- 3.0%, p < 0.001). By contrast, there was no significant difference between manifesting and nonmanifesting carriers of either genotype. Voxel-based analysis confirmed these findings and additionally revealed reduced RAC binding in the ventrolateral thalamus of both groups of mutation carriers. As in the striatum, the thalamic binding reductions were more pronounced in DYT6 carriers and were not influenced by the presence of clinical manifestations.
Reduced D(2) receptor availability in carriers of dystonia genes is compatible with dysfunction or loss of D(2)-bearing neurons, increased synaptic dopamine levels, or both. These changes, which may be present to different degrees in the DYT1 and DYT6 genotypes, are likely to represent susceptibility factors for the development of clinical manifestations in mutation carriers.
[Show abstract][Hide abstract] ABSTRACT: Monoamine dysfunction, particularly of the serotonin system, has been the dominant hypothesis guiding research and treatment development in affective disorders. The majority of research has been performed in midlife depressed adults. The importance of understanding the neurobiology of depression in older adults is underscored by increased rates of mortality and completed suicide and an increased risk of Alzheimer's dementia. To evaluate the dynamic response of the serotonin system, the acute effects of citalopram infusion on cerebral glucose metabolism was measured in depressed older adults and control subjects. The hypothesis was tested that smaller decreases in metabolism would be observed in cortical and limbic regions in depressed older adults relative to control subjects.
Sixteen depressed older adults and 13 control subjects underwent two resting positron emission tomography (PET) studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose after placebo and citalopram infusions.
In control subjects compared with depressed older adults, greater citalopram-induced decreases in cerebral metabolism were observed in the right anterior cingulate, middle temporal (bilaterally), left precuneus, and left parahippocampal gyri. Greater decreases in the depressed older adults than control subjects were observed in left superior and left middle frontal gyri and increases in left inferior parietal lobule, left cuneus, left thalamus, and right putamen.
In depressed older adults relative to control subjects, the cerebral metabolic response to citalopram is blunted in cortico-cortical and cortico-limbic pathways and increased in the left hemisphere (greater decrease interiorly and increases posteriorly). These findings suggest both blunted and compensatory cerebral metabolic responses to citalopram in depressed older adults.
Full-text · Article · May 2009 · Biological psychiatry
[Show abstract][Hide abstract] ABSTRACT: Pre-clinical and human neuropharmacological evidence suggests a role of cholinergic modulation of monoamines as a pathophysiological and therapeutic mechanism in Alzheimer's disease. The present study measured the effects of treatment with the cholinesterase inhibitor and nicotinic receptor modulator, galantamine, on the cerebral metabolic response to the selective serotonin reuptake inhibitor, citalopram. Seven probable Alzheimer's disease patients and seven demographically comparable controls underwent two positron emission tomography (PET) glucose metabolism scans, after administration of a saline placebo infusion (Day 1) and after citalopram (40 mg, IV, Day 2). The scan protocol was repeated in the Alzheimer's disease patients 2 months after titration to a 24 mg galantamine dose. At baseline, cerebral glucose metabolism was reduced in Alzheimer's disease patients relative to controls in right middle temporal, left posterior cingulate and parietal cortices (precuneus and inferior parietal lobule), as expected. Both groups demonstrated acute decreases in cerebral glucose metabolism after citalopram to a greater extent in the Alzheimer's disease patients. In the patients, relative to the controls, citalopram decreased glucose metabolism to a greater extent in middle frontal gyrus (bilaterally), left middle temporal gyrus and right posterior cingulate prior to treatment. Galantamine treatment alone increased metabolism in the right precuneus, right inferior parietal lobule and right middle occipital gyrus. In contrast, during galantamine treatment, citalopram increased metabolism in the right middle frontal gyrus, right post-central gyrus, right superior and middle temporal gyrus and right cerebellum. The combined cerebral metabolic effects of galantamine and citalopram suggest, consistent with preclinical data, a synergistic interaction of cholinergic and serotonergic systems.
[Show abstract][Hide abstract] ABSTRACT: The effect of a pharmacologic increase in serotonin concentrations on striatal dopamine (D2) receptor availability has been measured in several studies using positron emission tomography (PET) and the radiotracer [11C]-raclopride as a method for the in vivo imaging of serotonin modulation of striatal dopamine in human subjects. These studies have shown that an acute increase in serotonin concentrations produced a decrease in striatal D2 receptor availability. The current study was undertaken to measure the effects of a more pharmacologically selective serotonergic agent compared to previous studies, the serotonin reuptake inhibitor, citalopram, on striatal D2 receptor availability. Twelve healthy control subjects underwent two PET scans performed on the same day following i.v. administration of saline (Scan 1) and citalopram (Scan 2, 40 mg, i.v.). The [11C]-raclopride data were analyzed with a graphical analysis method using the cerebellum as the input function. Plasma levels of citalopram, cortisol, and prolactin were measured. The citalopram concentrations peaked at the end of infusion (EOI) and remained relatively consistent from 30 min to 3 h postinfusion. An increase in cortisol and prolactin concentrations was observed from the EOI until 60 min after the EOI. A significant decrease in striatal D2 receptor availability was observed after citalopram infusion (-5%), presumably due to an increase in endogenous dopamine concentrations. In summary, i.v. administration of the selective serotonin reuptake inhibitor, citalopram, produced modest reductions in striatal D2 receptor availability, consistent with other human [11C]-raclopride studies using less pharmacologically selective serotonergic agents.
[Show abstract][Hide abstract] ABSTRACT: Cannabis users have been reported to have decreased regional cerebral glucose metabolism after short periods of abstinence. The purpose of this study was to measure striatal dopamine receptor (D2/D3) availability and cerebral glucose metabolism with positron emission tomography (PET) in young adults who had a prolonged exposure to cannabis and who had been abstinent for a period of at least 12 weeks.
Six 18-21-year-old male subjects with cannabis dependence in early full remission and six age- and sex-matched healthy subjects underwent PET scans for D2/D3 receptor availability measured with [C11]-raclopride and glucose metabolism measured with [18F]-FDG. All subjects were sober for at least 12 weeks before PET scan procedures. PET data were analyzed with statistical parametric mapping software (SPM99; uncorrected p < 0.001, corrected p < 0.05 at the cluster level). Toxicology screening was performed prior to the PET scan to confirm the lack of drugs of abuse. OBSERVATION AND RESULTS: Striatal D2/D3 receptor availability did not differ significantly between groups. Compared to controls, subjects with cannabis dependence had lower normalized glucose metabolism in the right orbitofrontal cortex, putamen bilaterally, and precuneus. There were no significant correlations between striatal D2/D3 receptor availability and normalized glucose metabolism in any region of the frontal cortex or striatum.
These findings may reflect both cannabis exposure and adaptive changes that occur after a prolonged period of abstinence. Subsequent studies should address whether metabolic and dopamine receptor effects are associated with either active use or longer-term withdrawal in these relatively young subjects.
No preview · Article · May 2008 · Psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: To determine whether reduced striatal D2 receptor binding reported in patients with idiopathic torsion dystonia is associated with the genotype, the authors used PET and [11C]-raclopride to assess non-manifesting carriers of the DYT1 mutation. D2 receptor binding was reduced by approximately 15% in caudate and putamen (p < 0.005). These results suggest that striatal D2 binding reductions are a trait feature of the DYT1 genotype.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Feb 2004 · Nuclear Medicine and Biology
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
(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.
Preview · Article · Jul 2003 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
No preview · Article · Nov 2002 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Full-text · Article · Oct 2002 · American Journal of Geriatric Psychiatry
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: We have shown that fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane ([(18)F]FPCIT) and PET offer a valuable means of quantifying regional abnormality in dopamine transporter (DAT) imaging associated with Parkinson's disease (PD). The objective of this study was to delineate the topographic distribution of DAT binding in early stage idiopathic PD using statistical parametric analysis of [(18)F]FPCIT PET data. We performed dynamic PET studies in 15 hemi-parkinsonian (Hoehn & Yahr I) patients and 10 age-matched normal volunteers over 100 min and calculated images of [(18)F]FPCIT binding ratios on a pixel-by-pixel basis. Statistical parametric mapping (SPM) was then used to localize binding reductions in PD and to compute the absolute change relative to normal. [(18)F]FPCIT binding decreased significantly in the contralateral posterior putamen of the PD group (P < 0.001, corrected). A significant reduction was also seen in the ipsilateral putamen, which was smaller in extent but localized more posteriorly. A quantitative comparison of DAT binding in the two clusters showed that the onset of motor symptoms in PD was associated with an approximate 70% loss relative to the normal mean in the contralateral posterior putamen. These results suggest that SPM analysis of [(18)F]FPCIT PET data can be used to quantify and map abnormalities in DAT activity within the human striatum. This method provides a useful tool to track the onset and progression of PD at its earliest stages.