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author:("Ma, yinlong")
1.  A general strategy for developing cell-permeable photo-modulatable organic fluorescent probes for live-cell super-resolution imaging 
Nature Communications  2014;5:5573.
Single-molecule localization microscopy (SMLM) achieves super-resolution imaging beyond the diffraction limit but critically relies on the use of photo-modulatable fluorescent probes. Here we report a general strategy for constructing cell-permeable photo-modulatable organic fluorescent probes for live-cell SMLM by exploiting the remarkable cytosolic delivery ability of a cell-penetrating peptide (rR)3R2. We develop photo-modulatable organic fluorescent probes consisting of a (rR)3R2 peptide coupled to a cell-impermeable organic fluorophore and a recognition unit. Our results indicate that these organic probes are not only cell permeable but can also specifically and directly label endogenous targeted proteins. Using the probes, we obtain super-resolution images of lysosomes and endogenous F-actin under physiological conditions. We resolve the dynamics of F-actin with 10 s temporal resolution in live cells and discern fine F-actin structures with diameters of ~80 nm. These results open up new avenues in the design of fluorescent probes for live-cell super-resolution imaging.
Single-molecule localization microscopy depends on the use of photo-modulatable fluorescent probes; however, many cannot be used in live-cell studies due to poor cell permeability. Pan et al. present a strategy for constructing cell-permeable probes and use it to image actin filament dynamics and lysosomes.
doi:10.1038/ncomms6573
PMCID: PMC4263135  PMID: 25410769
2.  Co-expression analysis of differentially expressed genes in hepatitis C virus-induced hepatocellular carcinoma 
Molecular Medicine Reports  2014;11(1):21-28.
The aim of the current study was to investigate the molecular mechanisms underlying hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) using the expression profiles of HCV-infected Huh7 cells at different time points. The differentially expressed genes (DEGs) were identified with the Samr package in R software once the data were normalized. Functional and pathway enrichment analysis of the identified DEGs was also performed. Subsequently, MCODE in Cytoscape software was applied to conduct module analysis of the constructed co-expression networks. A total of 1,100 DEGs were identified between the HCV-infected and control samples at 12, 18, 24 and 48 h post-infection. DEGs at 24 and 48 h were involved in the same signaling pathways and biological processes, including sterol biosynthetic processes and tRNA amino-acylation. There were 22 time series genes which were clustered into 3 expression patterns, and the demarcation point of the 2 expression patterns that 401 overlapping DEGs at 24 and 48 h clustered into was 24 h post-infection. tRNA synthesis-related biological processes emerged at 24 and 48 h. Replication and assembly of HCV in HCV-infected Huh7 cells occurred mainly at 24 h post-infection. In view of this, the screened time series genes have the potential to become candidate target molecules for monitoring, diagnosing and treating HCV-induced HCC.
doi:10.3892/mmr.2014.2695
PMCID: PMC4237098  PMID: 25339452
hepatocellular carcinoma; hepatitis C virus; differentially expressed genes; time series genes; co-expression networks
3.  Parkinson’s Disease Cognitive Network Correlates with Caudate Dopamine 
NeuroImage  2013;78:204-209.
Prior evidence has suggested a link between caudate dopaminergic functioning and cognition in Parkinson’s disease (PD). In this dual tracer study we analyzed the relationship between nigrostriatal dopaminergic dysfunction and the expression of the previously validated PD cognition-related metabolic pattern (PDCP). In this study, 17 non-demented PD patients underwent positron emission tomography (PET) imaging with [18F]-fluorodeoxyglucose to measure PDCP expression, and [18F]-fluoropropyl-β-CIT (FPCIT) to measure dopamine transporter (DAT) binding. Automated voxel-by-voxel searches of the FPCIT PET volumes were performed to identify regions in which DAT binding significantly correlated with PDCP expression values. The findings were validated using prespecified anatomical regions-of-interest (ROIs). Voxel-wise interrogation of the FPCIT PET scans revealed a single significant cluster in which DAT binding correlated with PDCP expression (p<0.05, corrected). This cluster was localized to the left caudate nucleus; an analogous correlation (r=−0.63, p<0.01) was also present in the “mirror” region of the right hemisphere. These findings were confirmed by the presence of a significant correlation (r=−0.67, p<0.005) between PDCP expression and DAT binding in caudate ROIs, which survived adjustment for age, disease duration, and clinical severity ratings. Correlation between caudate DAT binding and subject expression of the PD motor-related metabolic pattern was not significant (p>0.21). In summary, this study demonstrates a significant relationship between loss of dopaminergic input to the caudate nucleus and the expression of a cognition-related disease network in unmedicated PD patients. These baseline measures likely function in concert to determine the cognitive effects of dopaminergic therapy in PD.
doi:10.1016/j.neuroimage.2013.03.070
PMCID: PMC3672243  PMID: 23578575
Parkinson’s disease; cognition; caudate; dopamine
4.  Abnormal metabolic network activity in REM sleep behavior disorder 
Neurology  2014;82(7):620-627.
Objective:
To determine whether the Parkinson disease–related covariance pattern (PDRP) expression is abnormally increased in idiopathic REM sleep behavior disorder (RBD) and whether increased baseline activity is associated with greater individual risk of subsequent phenoconversion.
Methods:
For this cohort study, we recruited 2 groups of RBD and control subjects. Cohort 1 comprised 10 subjects with RBD (63.5 ± 9.4 years old) and 10 healthy volunteers (62.7 ± 8.6 years old) who underwent resting-state metabolic brain imaging with 18F-fluorodeoxyglucose PET. Cohort 2 comprised 17 subjects with RBD (68.9 ± 4.8 years old) and 17 healthy volunteers (66.6 ± 6.0 years old) who underwent resting brain perfusion imaging with ethylcysteinate dimer SPECT. The latter group was followed clinically for 4.6 ± 2.5 years by investigators blinded to the imaging results. PDRP expression was measured in both RBD groups and compared with corresponding control values.
Results:
PDRP expression was elevated in both groups of subjects with RBD (cohort 1: p < 0.04; cohort 2: p < 0.005). Of the 17 subjects with long-term follow-up, 8 were diagnosed with Parkinson disease or dementia with Lewy bodies; the others did not phenoconvert. For individual subjects with RBD, final phenoconversion status was predicted using a logistical regression model based on PDRP expression and subject age at the time of imaging (r2 = 0.64, p < 0.0001).
Conclusions:
Latent network abnormalities in subjects with idiopathic RBD are associated with a greater likelihood of subsequent phenoconversion to a progressive neurodegenerative syndrome.
doi:10.1212/WNL.0000000000000130
PMCID: PMC3963420  PMID: 24453082
5.  Network modulation following sham surgery in Parkinson’s disease 
The Journal of Clinical Investigation  2014;124(8):3656-3666.
Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson’s disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify “sham-susceptible” subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.
doi:10.1172/JCI75073
PMCID: PMC4109544  PMID: 25036712
6.  Radiation Absorbed Dose to the Basal Ganglia from Dopamine Transporter Radioligand 18F-FPCIT 
BioMed Research International  2014;2014:498072.
Our previous dosimetry studies have demonstrated that for dopaminergic radiotracers, 18F-FDOPA and 18F-FPCIT, the urinary bladder is the critical organ. As these tracers accumulate in the basal ganglia (BG) with high affinity and long residence times, radiation dose to the BG may become significant, especially in normal control subjects. We have performed dynamic PET measurements using 18F-FPCIT in 16 normal adult subjects to determine if in fact the BG, although not a whole organ, but a well-defined substructure, receives the highest dose. Regions of interest were drawn over left and right BG structures. Resultant time-activity curves were generated and used to determine residence times for dosimetry calculations. S-factors were computed using the MIRDOSE3 nodule model for each caudate and putamen. For 18F-FPCIT, BG dose ranged from 0.029 to 0.069 mGy/MBq. In half of all subjects, BG dose exceeded 85% of the published critical organ (bladder) dose, and in three of those, the BG dose exceeded that for the bladder. The BG can become the dose-limiting organ in studies using dopamine transporter ligands. For some normal subjects studied with F-18 or long half-life radionuclide, the BG may exceed bladder dose and become the critical structure.
doi:10.1155/2014/498072
PMCID: PMC4100344  PMID: 25093172
7.  Metabolic imaging of bilateral anterior capsulotomy in refractory obsessive compulsive disorder: an FDG PET study 
The therapeutic benefits of bilateral capsulotomy for the treatment of refractory obsessive compulsive disorder (OCD) are probably attributed to interruption of the cortico-striato-thalamo-cortical circuitry. We evaluated resting brain metabolism and treatment response in OCD patients using positron emission tomography (PET) imaging. [18F]-fluoro-deoxy-glucose PET was performed in eight OCD patients precapsulotomy and postcapsulotomy. We determined metabolic differences between preoperative images in patients and those in eight age-matched healthy volunteers, and postoperative changes and clinical correlations in the patients. The OCD patients showed widespread metabolic increases in normalized glucose metabolism in the bilateral orbitofrontal cortex and inferior frontal gyrus, cingulate gyrus, and bilateral pons/cerebellum, and metabolic decreases bilaterally in the precentral and lingual gyri. Bilateral capsulotomy resulted in significant metabolic decreases bilaterally in the prefrontal cortical regions, especially in the dorsal anterior cingulate cortex (ACC) and in the medial dorsal thalamus and caudate nucleus. In contrast, metabolism increased bilaterally in the precentral and lingual gyri. Clinical improvement in patients correlated with metabolic changes in the bilateral dorsal ACC and in the right middle occipital gyrus after capsulotomy. This study underscores the importance of the internal capsule in modulating ventral prefrontal and dorsal anterior cingulate neuronal activity in the neurosurgical management of OCD patients.
doi:10.1038/jcbfm.2013.23
PMCID: PMC3677106  PMID: 23443174
anterior cingulate gyrus; bilateral capsulotomy; glucose metabolism; PET; refractory obsessive-compulsive disorder
8.  Longitudinal Studies of Cerebral Glucose Metabolism in Late-Life Depression and Normal Aging 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/gps.3840
PMCID: PMC3974580  PMID: 22740289
late-life depression; cerebral glucose metabolism; PET; citalopram; aging
9.  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.
doi:10.1371/journal.pone.0088119
PMCID: PMC3909315  PMID: 24498250
10.  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.
doi:10.1016/j.neuroimage.2012.08.039
PMCID: PMC3474325  PMID: 22951259
Parkinson’s disease; PET; Sleep
11.  SEROTONIN MODULATION OF CEREBRAL GLUCOSE METABOLISM: SEX AND AGE EFFECTS 
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.
doi:10.1002/syn.21590
PMCID: PMC3440524  PMID: 22836227
selective serotonin reuptake inhibitors; citalopram; serotonin; positron emission tomography (PET); glucose metabolism; sex differences; aging
12.  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.
doi:10.1523/JNEUROSCI.5024-12.2013
PMCID: PMC3671574  PMID: 23467370
13.  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.
doi:10.1172/JCI69411
PMCID: PMC3754266  PMID: 23985564
14.  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.
doi:10.1038/jcbfm.2011.166
PMCID: PMC3318142  PMID: 22126913
animal models; brain imaging; glucose; Parkinson's disease; positron emission tomography
15.  Dopamine cell transplantation in Parkinson's disease: challenge and perspective 
British Medical Bulletin  2011;100(1):173-189.
Background
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.
Conclusion
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.
doi:10.1093/bmb/ldr040
PMCID: PMC3276236  PMID: 21875864
cell transplantation; Parkinson's disease; regenerative medicine; emission tomography
16.  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.
doi:10.1021/jm200834x
PMCID: PMC3200116  PMID: 21905680
17.  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.
doi:10.1002/hbm.21135
PMCID: PMC3021765  PMID: 20886575
selective serotonin reuptake inhibitors; citalopram; serotonin; Positron Emission Tomography (PET); glucose metabolism; functional connectivity; partial least squares (PLS); depression; aging
18.  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.
doi:10.1016/j.neuroimage.2010.09.028
PMCID: PMC2997135  PMID: 20851193
Parkinson’s disease; positron emission tomography; tremor; Vim DBS; STN DBS
19.  The relationship between the acute cerebral metabolic response to citalopram and chronic citalopram treatment outcome 
Objectives
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.
Methods
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.
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 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
20.  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.
doi:10.1038/jcbfm.2009.256
PMCID: PMC2949137  PMID: 20051975
arterial spin labeling (ASL); cerebral blood flow (CBF); MRI; Parkinson's disease (PD); spatial covariance analysis
21.  Functional Polymorphism -31C/G in the Promoter of BIRC5 Gene and Risk of Nasopharyngeal Carcinoma among Chinese 
PLoS ONE  2011;6(2):e16748.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1371/journal.pone.0016748
PMCID: PMC3033414  PMID: 21304814
22.  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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.2967/jnumed.109.066811
PMCID: PMC2946843  PMID: 20008998
18F-FDOPA; PET; Parkinson’s disease; transplantation; long-term outcome
23.  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.
doi:10.1016/j.cbpa.2009.06.016
PMCID: PMC2748170  PMID: 19559806
hypoxia; arctic ground squirrels; brain oxygenation; brain tissue O2 partial pressure; brain temperature; O2 consumption; ventilation
24.  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.
doi:10.1016/j.neuroimage.2008.09.052
PMCID: PMC2946847  PMID: 18992824
25.  The Functional Neuroanatomy of Geriatric Depression 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/gps.2185
PMCID: PMC2730507  PMID: 19173332
Positron Emission Tomography (PET); glucose metabolism; depression; aging

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