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author:("Ma, yinlong")
1.  Longitudinal Studies of Cerebral Glucose Metabolism in Late-Life Depression and Normal Aging 
Late-life depression (LLD) has a substantial public health impact and is both a risk factor for and 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 7 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 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.
PMCID: PMC3974580  PMID: 22740289
late-life depression; cerebral glucose metabolism; PET; citalopram; aging
2.  Quantifying Significance of Topographical Similarities of Disease-Related Brain Metabolic Patterns 
PLoS ONE  2014;9(1):e88119.
Multivariate analytical routines have become increasingly popular in the study of cerebral function in health and in disease states. Spatial covariance analysis of functional neuroimaging data has been used to identify and validate characteristic topographies associated with specific brain disorders. Voxel-wise correlations can be used to assess similarities and differences that exist between covariance topographies. While the magnitude of the resulting topographical correlations is critical, statistical significance can be difficult to determine in the setting of large data vectors (comprised of over 100,000 voxel weights) and substantial autocorrelation effects. Here, we propose a novel method to determine the p-value of such correlations using pseudo-random network simulations.
PMCID: PMC3909315  PMID: 24498250
3.  Abnormal Network Topographies and Changes in Global Activity: Absence of a Causal Relationship 
NeuroImage  2012;63(4):1827-1832.
Changes in regional brain activity can be observed following global normalization procedures to reduce variability in the data. In particular, spurious regional differences may appear when scans from patients with low global activity are compared to those from healthy subjects. It has thus been suggested that the consistent increases in subcortical activity that characterize the abnormal Parkinson’s disease-related metabolic covariance pattern (PDRP) are artifacts of global normalization, and that similar topographies can be identified in scans from healthy subjects with varying global activity. To address this issue, we examined the effects of experimental reductions in global metabolic activity on PDRP expression. Ten healthy subjects underwent 18F-fluorodeoxyglucose PET in wakefulness and following sleep induction. In all subjects, the global metabolic rate (GMR) declined with sleep (mean −34%, range: −17 to −56%), exceeding the test-retest differences of the measure (p<0.001). By contrast, sleep-wake differences in PDRP expression did not differ from test-retest differences, and did not correlate (R2=0.04) with concurrent declines in global metabolic activity. Indeed, despite significant GMR reductions in sleep, PDRP values remained within the normal range. Likewise, voxel weights on the principal component patterns resulting from combined analysis of the sleep and wake scans did not correlate (R2<0.07) with the corresponding regional loadings on the PDRP topography. In aggregate, the data demonstrate that abnormal PDRP expression is not induced by reductions in global activity. Moreover, significant declines in GMR are not associated with the appearance of PDRP-like spatial topographies.
PMCID: PMC3474325  PMID: 22951259
Parkinson’s disease; PET; Sleep
Synapse (New York, N.Y.)  2012;66(11):955-964.
The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20–79 years) underwent two resting positron emission tomography (PET) studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([18F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response.
PMCID: PMC3440524  PMID: 22836227
selective serotonin reuptake inhibitors; citalopram; serotonin; positron emission tomography (PET); glucose metabolism; sex differences; aging
5.  Parkinson’s Disease: Increased Motor Network Activity in the Absence of Movement 
We used a network approach to assess systems-level abnormalities in motor activation in humans with Parkinson’s disease (PD). This was done by measuring the expression of the normal movement-related activation pattern (NMRP), a previously validated activation network deployed by healthy subjects during motor performance. In this study, NMRP expression was prospectively quantified in 15O-water PET scans from a PD patient cohort comprised of a longitudinal early stage group (n=12) scanned at baseline and at 2–3 follow-up visits two years apart, and a moderately advanced group scanned on and off treatment with either subthalamic nucleus (STN) deep brain stimulation (n=14) or intravenous levodopa infusion (n=14). For each subject and condition, we measured NMRP expression during both movement and rest. Resting expression of the abnormal PD-related metabolic covariance pattern (PDRP) was likewise determined in the same subjects.
NMRP expression was abnormally elevated (p<0.001) in PD patients scanned in the non-movement rest state. By contrast, network activity measured during movement did not differ from normal (p=0.34). In the longitudinal cohort, abnormal increases in resting NMRP expression were evident at the earliest clinical stages (p<0.05), which progressed significantly over time (p=0.003). Analogous network changes were present at baseline in the treatment cohort (p=0.001). These abnormalities improved with STN stimulation (p<0.005) but not levodopa (p=0.25). In both cohorts, the changes in NMRP expression that were observed did not correlate with concurrent PDRP measurements (p>0.22). Thus, the resting state in PD is characterized by changes in the activity of normal as well as pathological brain networks.
PMCID: PMC3671574  PMID: 23467370
6.  Metabolic network as a progression biomarker of premanifest Huntington’s disease 
The Journal of Clinical Investigation  2013;123(9):4076-4088.
Background. The evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network associated with the progression of preclinical Huntington’s disease (HD).
Methods. Twelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue volume. The rate of metabolic network progression in this cohort was compared with the corresponding estimate obtained in a separate group of 21 premanifest HD carriers who were scanned twice over a 2-year period.
Results. In the original premanifest cohort, network analysis disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approximately twice the rate of single region measurements from the same subjects.
Conclusion. Metabolic network measurements provide a sensitive means of quantitatively evaluating disease progression in premanifest individuals. This approach may be incorporated into clinical trials to assess disease-modifying agents.
Trial registration. Registration is not required for observational studies.
Funding. NIH (National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering) and CHDI Foundation Inc.
PMCID: PMC3754266  PMID: 23985564
7.  Abnormal metabolic brain networks in a nonhuman primate model of parkinsonism 
Parkinson's disease (PD) is associated with a characteristic regional metabolic covariance pattern that is modulated by treatment. To determine whether a homologous metabolic pattern is also present in nonhuman primate models of parkinsonism, 11 adult macaque monkeys with parkinsonism secondary to chronic systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 12 age-matched healthy animals were scanned with [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). A subgroup comprising five parkinsonian and six control animals was used to identify a parkinsonism-related pattern (PRP). For validation, analogous topographies were derived from other subsets of parkinsonian and control animals. The PRP topography was characterized by metabolic increases in putamen/pallidum, thalamus, pons, and sensorimotor cortex, as well as reductions in the posterior parietal-occipital region. Pattern expression was significantly elevated in parkinsonian relative to healthy animals (P<0.00001). Parkinsonism-related topographies identified in the other derivation sets were very similar, with significant pairwise correlations of region weights (r>0.88; P<0.0001) and subject scores (r>0.74; P<0.01). Moreover, pattern expression in parkinsonian animals correlated with motor ratings (r>0.71; P<0.05). Thus, homologous parkinsonism-related metabolic networks are demonstrable in PD patients and in monkeys with experimental parkinsonism. Network quantification may provide a useful biomarker for the evaluation of new therapeutic agents in preclinical models of PD.
PMCID: PMC3318142  PMID: 22126913
animal models; brain imaging; glucose; Parkinson's disease; positron emission tomography
8.  Dopamine cell transplantation in Parkinson's disease: challenge and perspective 
British Medical Bulletin  2011;100(1):173-189.
Functional imaging provides a valuable adjunct to clinical evaluation for assessing the efficacy of cell-based restorative therapies in Parkinson's disease (PD).
Sources of data
In this article, we review the latest advances on the use of positron emission tomography (PET) imaging in evaluating the surgical outcome of embryonic dopamine (DA) cell transplantation in PD patients.
Areas of agreement
These studies suggest long-term cell survival and clinical benefit following striatal transplantation of fetal nigral tissue in PD patients and in models of experimental parkinsonism.
Areas of controversy
Adverse events subsequent to transplantation have also been noted and attributed to a variety of causes.
Growing points
Optimal outcomes of DA cell transplantation therapies are dependent on tissue composition and phenotype of DA neurons in the graft.
Areas timely for developing research
Given continued progress in DA neuron production from stem cells in recent years, transplantation of neural stem cells may be the next to enter clinical trials in patients.
The existing data from studies of embryonic DA transplantation for advanced PD have provided valuable insights for the design of new cell-based therapies for the treatment of this and related neurodegenerative disorders.
PMCID: PMC3276236  PMID: 21875864
cell transplantation; Parkinson's disease; regenerative medicine; emission tomography
9.  Deconstruction of the α4β2 Nicotinic Acetylchloine (nACh) Receptor Positive Allosteric Modulator des-Formylflustrabromine (dFBr) 
Journal of medicinal chemistry  2011;54(20):7259-7267.
des -Formylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of α4β2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using 2-electrode voltage clamp techniques. Although the intact structure of 1 was found optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity. In particular, reduction of the olefinic side chain of 1, as seen with 6, not only resulted in retention of activity/potency but in enhanced selectivity for α4β2 versus α7 nACh receptors. Pharmacophoric features for the allosteric modulation of α4β2 nACh receptors by 1 were identified.
PMCID: PMC3200116  PMID: 21905680
10.  Distinct Functional Networks Associated with Improvement of Affective Symptoms and Cognitive Function During Citalopram Treatment in Geriatric Depression 
Human brain mapping  2010;32(10):1677-1691.
Variability in the affective and cognitive symptom response to antidepressant treatment has been observed in geriatric depression. The underlying neural circuitry is poorly understood. The current 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 eight 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.
PMCID: PMC3021765  PMID: 20886575
selective serotonin reuptake inhibitors; citalopram; serotonin; Positron Emission Tomography (PET); glucose metabolism; functional connectivity; partial least squares (PLS); depression; aging
11.  Parkinson’s Disease Tremor-Related Metabolic Network: Characterization, Progression, and Treatment Effects 
NeuroImage  2010;54(2):1244-1253.
The circuit changes that mediate parkinsonian tremor, while likely differing from those underlying akinesia and rigidity, are not precisely known. In this study, to identify a specific metabolic brain network associated with this disease manifestation, we used FDG PET to scan nine tremor dominant Parkinson’s disease (PD) patients at baseline and during ventral intermediate (Vim) thalamic nucleus during deep brain stimulation (DBS). Ordinal trends canonical variates analysis (OrT/CVA) was performed on the within-subject scan data to detect a significant spatial covariance pattern with consistent changes in subject expression during stimulation-mediated tremor suppression. The metabolic pattern was characterized by covarying increases in the activity of the cerebellum/dentate nucleus and primary motor cortex, and, to a less degree, the caudate/putamen. Vim stimulation resulted in consistent reductions in pattern expression (p<0.005, permutation test). In the absence of stimulation, pattern expression values (subject scores) correlated significantly (r=0.85, p<0.02 with concurrent accelerometric measurements of tremor amplitude.
To validate this spatial covariance pattern as an objective network biomarker of PD tremor, we prospectively quantified its expression on an individual subject basis in independent PD populations. The resulting subject scores for this PD tremor-related pattern (PDTP) were found to exhibit: (1) excellent test-retest reproducibility (p<0.0001); (2) significant correlation with independent clinical ratings of tremor (r=0.54, p<0.001) but not akinesia-rigidity; and (3) significant elevations (p<0.02) in tremor dominant relative to atremulous PD patients.
Following validation, we assessed the natural history of PDTP expression in early stage patients scanned longitudinally with FDG PET over a four year interval. Significant increases in PDTP expression (p<0.01) were evident in this cohort over time; rate of progression, however, was slower than for the PD-related akinesia/rigidity pattern (PDRP). We also determined whether PDTP expression is modulated by interventions specifically directed at parkinsonian tremor. While Vim DBS was associated with changes in PDTP (p<0.001) but not PDRP expression, subthalamic nucleus (STN) DBS reduced the activity of both networks (p<0.05). PDTP expression was suppressed more by Vim than by STN stimulation (p<0.05).
These findings suggest that parkinsonian tremor is mediated by a distinct metabolic network involving primarily cerebello-thalamo-cortical pathways. Indeed, effective treatment of this symptom is associated with significant reduction in PDTP expression. Quantification of treatment-mediated changes in both PDTP and PDRP scores can provide an objective means of evaluating the differential effects of novel antiparkinsonian interventions on the different motor features of the disorder.
PMCID: PMC2997135  PMID: 20851193
Parkinson’s disease; positron emission tomography; tremor; Vim DBS; STN DBS
12.  The relationship between the acute cerebral metabolic response to citalopram and chronic citalopram treatment outcome 
The ability to identify the early neurobiological markers to predict the clinical response to a course of chronic psychotropic drug treatment motivated the early development of neurochemical brain imaging methods. The present study tested the hypothesis that lower baseline glucose metabolism and greater acute cerebral metabolic responses to a single, intravenous dose of the selective serotonin reuptake inhibitor (SSRI) citalopram would be associated with greater antidepressant response to twelve 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 (40mg, IV). Then, the patients were treated with the oral medication for twelve 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 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.
PMCID: PMC3058257  PMID: 21218565
13.  Parkinson's disease spatial covariance pattern: noninvasive quantification with perfusion MRI 
Parkinson's disease (PD) is associated with elevated expression of a specific disease-related spatial covariance pattern (PDRP) in radiotracer scans of cerebral blood flow and metabolism. In this study, we scanned nine early-stage patients with PD and nine healthy controls using continuous arterial spin labeling (CASL) perfusion magnetic resonance imaging (pMRI). Parkinson's disease-related metabolic pattern expression in CASL pMRI scans was compared with the corresponding 18F-fluorodeoxyglucose positron emission tomography values. The PDRP expression was abnormally elevated (P<0.01) in patients scanned with either modality, and the two values were highly intercorrelated (P<0.0001). Perfusion MRI methods can be used for accurate quantification of disease-related covariance patterns.
PMCID: PMC2949137  PMID: 20051975
arterial spin labeling (ASL); cerebral blood flow (CBF); MRI; Parkinson's disease (PD); spatial covariance analysis
14.  Functional Polymorphism -31C/G in the Promoter of BIRC5 Gene and Risk of Nasopharyngeal Carcinoma among Chinese 
PLoS ONE  2011;6(2):e16748.
Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5, also called as survivin) is a member of the inhibitor of apoptosis protein (IAP) family, which plays an important role in the occurrence and progression of cancer. Recently, a polymorphism in the promoter of BIRC5, -31C/G (rs9904341), was shown to influence BIRC5 expression.
We examined whether the -31C/G was related to the risk of developing nasopharyngeal carcinoma (NPC) in a case-control population from Guangxi province in southern China, which consists of 855 patients with NPC and 1036 controls. This polymorphism was genotyped by TaqMan assay. The genetic associations with the occurrence and progression of NPC were estimated by logistic regression.
We observed a statistically significant increased occurrence of NPC associated with the CC genotype (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.13–1.73; P = 0.0020) compared with the genotypes containing G allele (CG + GG genotype). However, no significant association was observed for the -31C/G with the severity of NPC (as measured by tumor-node-metastasis staging system).
Our findings suggest that the functional polymorphism -31C/G in the promoter of BIRC5 gene may play a role in mediating the susceptibility to NPC among Chinese.
PMCID: PMC3033414  PMID: 21304814
15.  Dopamine Cell Implantation in Parkinson’s Disease: Long-Term Clinical and 18F-FDOPA PET Outcomes 
We have previously reported the results of a 1-y double-blind, placebo-controlled study of embryonic dopamine cell implantation for Parkinson’s disease. At the end of the blinded phase, we found a significant increase in putamen uptake on 18F-fluorodopa (18F-FDOPA) PET reflecting the viability of the grafts. Nonetheless, clinical improvement was significant only in younger (age ≤ 60 y) transplant recipients, as indicated by a reduction in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores.
We now report long-term clinical and PET outcomes from 33 of the original trial participants who were followed for 2 y after transplantation and 15 of these subjects who were followed for 2 additional years. Longitudinal changes in UPDRS motor ratings and caudate and putamen 18F-FDOPA uptake were assessed with repeated-measures ANOVA. Relationships between these changes over time were evaluated by the analysis of within-subject correlations.
We found that UPDRS motor ratings declined over time after transplantation (P < 0.001). Clinical improvement at 1 y was relatively better for the younger transplant recipients and for men, but these age and sex differences were not evident at longer-term follow-up. Significant increases in putamen 18F-FDOPA uptake were evident at all posttransplantation time points (P < 0.001) and were not influenced by either age or sex. Posttransplantation changes in putamen PET signal and clinical outcome were significantly intercorrelated (P < 0.02) over the course of the study. Image analysis at the voxel level revealed significant bilateral increases in 18F-FDOPA uptake at 1 y (P < 0.001) in the posterior putamen engraftment sites. PET signal in this region increased further at 2 and 4 y after engraftment. Concurrently, this analysis disclosed progressive declines in radiotracer uptake in the nonengrafted caudate and ventrorostral putamen. Clinical improvement after transplantation correlated with the retention of PET signal in this region at the preoperative baseline.
These results suggest that clinical benefit and graft viability are sustained up to 4 y after transplantation. Moreover, the dependence of clinical (but not imaging) outcomes on subject age and sex at 1 y may not persist over the long term. Last, the imaging changes reliably correlate with clinical outcome over the entire posttransplantation time course.
PMCID: PMC2946843  PMID: 20008998
18F-FDOPA; PET; Parkinson’s disease; transplantation; long-term outcome
16.  Adaptive response of brain tissue oxygenation to environmental hypoxia in non-sedated, non-anesthetized arctic ground squirrels 
The present study examined the physiological mechanisms of the responses of brain tissue oxygen partial pressure (PtO2), brain temperature (Tbrain), global oxygen consumption V̇o2, and respiratory frequency (fR) to hypoxia in non-sedated and non-anesthetized arctic ground squirrels (Spermophilus parryii, AGS) and rats. We found that 1) in contrast to oxygen partial pressure in blood (PaO2), the baseline value of PtO2 in summer euthermic AGS is significantly higher than in rats; 2) both PtO2 and PaO2 are dramatically reduced by inspired 8% O2 in AGS and rats, but AGS have a greater capacity in PtO2 to cope with environmental hypoxia; 3) metabolic rate before, during, and after hypoxic exposure is consistently lower in AGS than in rats; 4) the respiratory responding patterns to hypoxia in the two species differ in that fR decreases in AGS but increases in rats. These results suggest that 1) AGS have special mechanisms to maintain higher PtO2 and lower PaO2, and these levels in AGS represent a typical pattern of adaptation of heterothermic species to and a brain protection from hypoxia; 2) AGS brain responds to hypoxia through greater decreases in PtO2 and decreased fR and ventilation. In contrast, rat brain responds to hypoxia by less reduction in PtO2 and increased fR and ventilation.
PMCID: PMC2748170  PMID: 19559806
hypoxia; arctic ground squirrels; brain oxygenation; brain tissue O2 partial pressure; brain temperature; O2 consumption; ventilation
17.  Abnormal Regional Brain Function in Parkinson’s Disease: Truth or Fiction? 
NeuroImage  2008;45(2):260-266.
Normalization of regional measurements by the global mean is commonly employed to minimize inter-subject variability in functional imaging studies. This practice is based on the assumption that global values do not substantially differ between patient and control groups. Borghammer and colleagues challenge the validity of this assumption. They focus on Parkinson’s disease (PD) and use computer simulations to show that lower global values can produce spurious increases in subcortical brain regions. The authors speculate that the increased signal observed in these areas in PD patients is artifactual and unrelated to localized physiological changes in brain function. In this commentary, we summarize what is currently known of the relationship between regional and global metabolic activity in PD and experimental parkinsonism. Using SPM, we found that early PD patients demonstrated significant elevations in globally normalized metabolic activity localized to a discrete set of biologically relevant subcortical areas, despite virtually identical global metabolism in these patients and age-matched healthy controls. Group differences in the corresponding absolute measures were not detected because of their greater variability. Over time, abnormal increases in normalized (but not absolute) metabolic activity in subcortical regions appeared earlier in the course of disease and progressed faster than focal cortical reductions or declines in global values. These results indicate that subcortical elevations in normalized regional metabolism are not artifactual. In fact, these measures prove to be more sensitive than absolute values in detecting meaningful functional abnormalities in this disease. Multivariate analysis revealed that the abnormal spatial covariance structure of early PD is dominated by subcortical increases, which were not driven by reductions in cortical or global metabolic activity. Because of the stability of the network measurements, these indices are better suited for use as imaging biomarkers of PD progression and treatment efficacy.
PMCID: PMC2946847  PMID: 18992824
18.  The Functional Neuroanatomy of Geriatric Depression 
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 thirteen 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 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.
PMCID: PMC2730507  PMID: 19173332
Positron Emission Tomography (PET); glucose metabolism; depression; aging
19.  Serotonin Modulation of Cerebral Glucose Metabolism in Depressed Older Adults 
Biological psychiatry  2009;66(3):259-266.
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 mid-life 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 controls.
Sixteen depressed older adults and thirteen controls underwent two resting Positron Emission Tomography (PET) studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose after placebo and citalopram infusions.
In controls compared to 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 controls was 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 controls, the cerebral metabolic response to citalopram is blunted in cortico-cortico and cortico-limbic pathways and increased in the left hemisphere (greater decrease interiorly and increases posterior). These findings suggest both blunted and compensatory cerebral metabolic responses to citalopram in depressed older adults.
PMCID: PMC2706292  PMID: 19368900
selective serotonin reuptake inhibitors; citalopram; serotonin; Positron Emission Tomography (PET); glucose metabolism; depression; aging
20.  The Cerebral Glucose Metabolic Response to Combined Total Sleep Deprivation and Antidepressant Treatment in Geriatric Depression: A Randomized, Placebo Controlled Study 
Psychiatry research  2008;171(1):1-9.
A randomized, placebo controlled study was performed to evaluate whether the onset of the glucose metabolic effects of a selective serotonin reuptake inhibitor (paroxetine) would be accelerated by total sleep deprivation (TSD). Patients were randomly assigned to one of three groups: TSD and paroxetine treatment, TSD and two weeks of placebo followed by paroxetine treatment, or two weeks of paroxetine treatment. Sixteen elderly depressed patients who met DSM-IV criteria for major depressive disorder and nine age-matched comparison subjects underwent Positron Emission Tomography (PET) studies of cerebral glucose metabolism at baseline, post-TSD (or a normal night’s sleep for the paroxetine only group), post-recovery sleep and two weeks post-paroxetine or placebo treatment (patients only). TSD was not consistently associated with a decrease in depressive symptoms between groups nor with decreases in cerebral metabolism in cortical regions that have been associated with rapid and sustained clinical improvement (e.g. anterior cingulate gyrus). The observation of a synergistic antidepressant effect of combined TSD and paroxetine treatment that was observed in a previous “open label”, pilot study was not observed in the present randomized study, consistent with lack of a cerebral metabolic effect in brains regions previously shown to be associated with improvement of depressive symptoms.
PMCID: PMC2878400  PMID: 19087899
geriatric depression; selective serotonin reuptake inhibitors; placebo; sleep deprivation; Positron Emission Tomography(PET); glucose metabolism
21.  Cholinergic modulation of the cerebral metabolic response to citalopram in Alzheimer's disease 
Brain  2009;132(2):392-401.
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.
PMCID: PMC2640217  PMID: 19153152
Alzheimer's disease; positron emission tomography (PET); acetylcholine; serotonin; citalopram; galantamine
22.  Simultaneous measurement of brain tissue oxygen partial pressure, temperature, and global oxygen consumption during hibernation, arousal, and euthermy in non-sedated and non-anesthetized Arctic ground squirrels 
Journal of neuroscience methods  2008;174(2):237-244.
This study reports an online temperature correction method for determining tissue oxygen partial pressure (PtO2) in the striatum and a novel simultaneous measurement of brain PtO2 and temperature (Tbrain) in conjunction with global oxygen consumption (VO2) in non-sedated and non-anesthetized freely moving Arctic ground squirrels (AGS, Spermophilus parryii). This method fills an important research gap—the lack of a suitable method for physiologic studies of tissue PO2 in hibernating or other cool-blooded species.
PtO2 in AGS brain during euthermy (21.22 ± 2.06 mm Hg) is significantly higher (P=0.016) than during hibernation (13.21 ± 0.46 mm Hg) suggests brain oxygenation in the striatum is normoxic during euthermy and hypoxic during hibernation. These results in PtO2 are different from blood oxygen partial pressure (PaO2) in AGS, which are significantly lower during euthermy than during hibernation and are actually hypoxic during euthermy and normoxic during hibernation in our previous study. This intriguing difference between the PO2 of brain tissue and blood during these two physiological states suggests that regional mechanisms in the brain play a role in maintaining tissue oxygenation and protect against hypoxia during hibernation.
PMCID: PMC2615241  PMID: 18722471
Temperature correction; Correction factor; Online calculation; Tissue O2 partial pressure; Simultaneous multi-measurements; Real-time; In-vivo
23.  Dissociation of Metabolic and Neurovascular Responses to Levodopa in the Treatment of Parkinson’s Disease 
We compared the metabolic and neurovascular effects of levodopa (LD) therapy for Parkinson’s disease (PD). Eleven PD patients were scanned with both [15O]-H2O and [18F]-FDG PET in the unmedicated state and during intravenous LD infusion. Images were used to quantify LD-mediated changes in the expression of motor- and cognition-related PD covariance patterns in scans of cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR). These changes in network activity were compared with those occurring during subthalamic nucleus deep brain stimulation (STN DBS), and those observed in a test-retest PD control group. Separate voxel-based searches were conducted to identify individual regions with dissociated treatment-mediated changes in local cerebral blood flow and metabolism.
We found a significant dissociation between CBF and CMR in the modulation of the PD motor-related network by LD treatment (p<0.001). This dissociation was characterized by reductions in network activity in the CMR scans (p<0.003) occurring concurrently with increases in the CBF scans (p<0.01). Flow-metabolism dissociation was also evident at the regional level, with LD-mediated reductions in CMR and increases in CBF in the putamen/globus pallidus, dorsal midbrain/pons, STN, and ventral thalamus. CBF responses to LD in the putamen and pons were relatively greater in patients exhibiting drug- induced dyskinesia. By contrast, flow-metabolism dissociation was not present in the STN DBS treatment group or in the PD control group. These findings suggest that flow-metabolism dissociation is a distinctive feature of LD treatment. This phenomenon may be especially pronounced in patients with LD-induced dyskinesia.
PMCID: PMC2577921  PMID: 18417699
Parkinson’s disease; positron emission tomography; glucose metabolism; cerebral blood flow; levodopa treatment; STN DBS
24.  Preclinical Huntington's Disease: Compensatory Brain Responses during Learning 
Annals of neurology  2006;59(1):53-59.
Motor sequence learning is abnormal in presymptomatic Huntington's disease (p-HD). The neural substrates underlying this early manifestation of HD are poorly understood. To study the mechanism of this cognitive abnormality in p-HD, we used positron emission tomography to record brain activity during motor sequence learning in these subjects. Eleven p-HD subjects (age, 45.8 ± 11.0 years; CAG repeat length, 41.6 ± 1.8) and 11 age-matched control subjects (age, 45.3 ± 13.4 years) underwent H2 15O positron emission tomography while performing a set of kinematically controlled motor sequence learning and execution tasks. Differences in regional brain activation responses between groups and conditions were assessed. In addition, we identified discrete regions in which learning-related activity correlated with performance. We found that sequence learning was impaired in p-HD subjects despite normal motor performance. In p-HD, activation responses during learning were abnormally increased in the left mediodorsal thalamus and orbitofrontal cortex (OFC; BA 11/47). Impaired learning performance in these subjects was associated with increased activation responses in the precuneus (BA 18/31). These data suggest that enhanced activation of thalamocortical pathways during motor learning can compensate for caudate degeneration in p-HD. Nonetheless, this mechanism may not be sufficient to sustain a normal level of task performance, even during the presymptomatic stage of the disease.
PMCID: PMC2519955  PMID: 16261565

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