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Biomedical subjects

Linda Chang

Publications and source records attributed to Linda Chang.

34 records · Page 2Linked to original sources
PubMed2004

Adaptation of the attention network in human immunodeficiency virus brain injury.

Human immunodeficiency virus (HIV)-positive patients commonly have attention and concentration problems. However, it remains unclear how HIV infection affects the attention network. Therefore, blood oxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI) was performed in 36 subjects (18 HIV and 18 seronegative [SN] controls) during a set of visual attention tasks with increasing levels of attentional load. Compared with SN controls, HIV subjects showed similar task performance (accuracies and reaction times) but decreased activation in the normal visual attention network (dorsal parietal, bilateral prefrontal, and cerebellar regions) and increased activation in adjacent or contralateral brain regions. Cognitive performance (assessed with NPZ-8), CD4, and viral load all correlated with activated BOLD signals in brain regions that activated more in HIV subjects. Furthermore, HIV subjects activated more than SN controls in brain regions that showed load-dependent increase in activation (right prefrontal and right parietal regions) but less in regions that showed a saturation effect with increasing load. These findings suggest that HIV-associated brain injury leads to reduced efficiency in the normal attention network, thus requiring reorganization and increased usage of neural reserves to maintain performance during attention-requiring tasks. Exceeding the brain reserve capacity may lead to attention deficits and cognitive impairment in HIV patients.

Adult↗
PubMed2004

Regional patterns of brain metabolites in AIDS dementia complex.

The relationship of the cellular changes in the HIV-infected brain to the onset and progression of AIDS dementia complex (ADC) remains uncertain. We undertook an in vivo proton magnetic resonance spectroscopy (MRS) study and used factor analysis to identify specific cellular and regional brain changes that may serve as metabolic markers of ADC. The ratio of N-acetyl aspartate (NAA), choline (Cho), and myoinositol (MI) over creatine (Cr), markers of neuronal and glial cell metabolism, were measured in the basal ganglia, centrum semiovale, and parietal cortex from 100 subjects with and without ADC. Three metabolic patterns were identified, which we termed "inflammatory" (mainly MI/Cr elevations in all three regions plus Cho/Cr increases in the centrum semiovale and parietal cortex), "basal ganglia" (mostly NAA/Cr and Cho/Cr elevations in the basal ganglia), and "neuronal" (primarily NAA/Cr reductions in the centrum semiovale and the parietal cortex). Logistic regression analysis revealed that, adjusted for age, basal ganglia and neuronal pattern scores were strongly associated with ADC but inflammatory levels were not. We conclude that by using factor analysis, we are able to combine multiple metabolites across brain regions in a biologically plausible manner and construct a predictive model of ADC adjusting for relevant factors such as age.

AIDS Dementia Complex↗
PubMed2004

Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression.

Although previous studies demonstrate that appropriate Notch signaling is required during angiogenesis and in vascular homeostasis, the mechanisms by which Notch regulates vascular function remain to be elucidated. Here, we show that activation of the Notch pathway by the ligand Jagged1 reduces the proliferation of endothelial cells. Notch activation inhibits proliferation of endothelial cells in a cell-autonomous manner by inhibiting phosphorylation of the retinoblastoma protein (Rb). During cell cycle entry, p21Cip1 is upregulated in endothelial cells. Activated Notch inhibits mitogen-induced upregulation of p21Cip1 and delays cyclin D-cdk4-mediated Rb phosphorylation. Notch-dependent repression of p21Cip1 prevents nuclear localization of cyclin D and cdk4. The necessity of p21Cip1 for nuclear translocation of cyclin D-cdk4 and S-phase entry in endothelial cells was demonstrated by targeted downregulation of p21Cip1 by using RNA interference. We further demonstrate that when endothelial cells reach confluence, Notch is activated and p21Cip1 is downregulated. Inhibition of the Notch pathway at confluence prevents p21Cip1 downregulation and induces Rb phosphorylation. We suggest that Notch activation contributes to contact inhibition of endothelial cells, in part through repression of p21Cip1 expression.

Active Transport, Cell Nucleus↗
PubMed2004

Partial recovery of brain metabolism in methamphetamine abusers after protracted abstinence.

OBJECTIVE: Methamphetamine is a highly addictive drug of abuse that is neurotoxic to dopamine terminals. The authors recently reported that decreases in dopamine transporters (used as markers of dopamine terminals) in the striatum of methamphetamine abusers recover with protracted abstinence and that relative to comparison subjects, recently detoxified methamphetamine abusers have lower metabolism in the striatum and thalamus. In this study, the authors assessed whether metabolism recovers with protracted abstinence. METHOD: Brain glucose metabolism was measured with positron emission tomography and [18F]fluorodeoxyglucose in five methamphetamine abusers who were evaluated after both a short (<6 months) and protracted (12-17 months) abstinence interval, eight methamphetamine abusers tested only after protracted abstinence, and 11 comparison subjects who were not drug users. RESULTS: Significantly greater thalamic, but not striatal, metabolism was seen following protracted abstinence relative to metabolism assessed after a short abstinence interval, and this increase was associated with improved performance in motor and verbal memory tests. Relative to the comparison subjects, the methamphetamine abusers tested after protracted abstinence had lower metabolism in the striatum (most accentuated in the caudate and nucleus accumbens) but not in the thalamus. CONCLUSIONS: The persistent decreases in striatal metabolism in methamphetamine abusers could reflect long-lasting changes in dopamine cell activity, and decreases in the nucleus accumbens could account for the persistence of amotivation and anhedonia in detoxified methamphetamine abusers. The recovery of thalamic metabolism could reflect adaptation responses to compensate for the dopamine deficits, and the associated improvement in neuropsychological performance further indicates its functional significance. These results suggest that while protracted abstinence may reverse some of the methamphetamine-induced alterations in brain function, other deficits persist.

Adaptation, Physiological↗
PubMed2004

Antiretroviral treatment alters relationship between MCP-1 and neurometabolites in HIV patients.

OBJECTIVE: The relationships between neurometabolites and macrophage chemoattractant protein (MCP-1) in serum and cerebrospinal fluid (CSF) were evaluated in HIV patients before and after antiretroviral treatment. DESIGN: Prior studies found higher CSF MCP-1 levels in patients with HIV-associated dementia compared to those in neuroasymptomatic. We hypothesized that CSF MCP-1 levels would correlate inversely to neuronal metabolites [including N-acetyl compounds, glutamate+glutamine, as assessed by principal component analyses (PCA)] and positively to glial metabolites (including myo-inositol and choline compounds). METHODS: Thirty-nine antiretroviral-naive HIV patients were evaluated prospectively with proton magnetic resonance spectroscopy (1H MRS), and serum and CSF MCP-1 measurements prior to highly active antiretroviral therapy (HAART); 31 of these patients completed follow-up studies after 3 months of HAART but only 24 had follow-up CSF studies. RESULTS: After HAART, brain metabolites and clinical signs showed no change despite improvements in systemic (CD4 counts, plasma viral load, MCP-1) and CSF (viral load and MCP-1) variables. CSF, but not serum, MCP-1 levels correlated inversely with the neuronal component (from PCA) prior to treatment (r=-0.59, P=0.0008). Conversely, after 3 months of HAART, the glial component (from PCA) correlated positively with CSF MCP-1 levels (r=0.70, P=0.0002; ANCOVA interaction for treatment status, P=0.003). CONCLUSIONS: These findings suggest that higher CSF MCP-1 levels are associated with neuronal dysfunction in untreated patients. After 3 months of HAART, the decreased systemic factors (viral burden, systemically derived MCP-1) no longer associate with neuronal dysfunction, but subjects with the strongest glial response in the brain continue to produce the highest levels of MCP-1.

AIDS Dementia Complex↗
PubMed2003

A multi-center 1H MRS study of the AIDS dementia complex: validation and preliminary analysis.

PURPOSE: To demonstrate the technical feasibility and reliability of a multi-center study characterizing regional levels of the brain metabolite ratios choline (Cho)/creatine (Cr) and myoinositol (MI)/Cr, markers of glial cell activity, and N-acetyl aspartate (NAA)/Cr, a marker of mature neurons, in subjects with AIDS dementia complex (ADC). MATERIALS AND METHODS: Using an automated protocol (GE PROBE-P), short echo time spectra (TE = 35 msec) were obtained at eight sites from uniformly prepared phantoms and from three brain regions (frontal white matter, basal ganglia, and parietal cortex) of normal volunteers and ADC and HIV-negative subjects. RESULTS: A random-effects model of the phantom and volunteer data showed no significant inter-site differences. Feasibility of a multi-center study was further validated by detection of significant differences between the metabolite ratios of ADC subjects and HIV-negative controls. ADC subjects exhibited significantly higher Cho/Cr and MI/Cr in the basal ganglia and significantly reduced NAA/Cr and significantly higher MI/Cr in the frontal white matter. These results are consistent with the predominantly subcortical distribution of the pathologic abnormalities associated with ADC. CONCLUSION: This is the first study to ascertain and validate the reliability and reproducibility of a short echo time (1)H-MRS acquisition sequence from multiple brain regions in a multi-center setting. It should now be possible to examine the regional effects of HIV infection in the brain in a large number of subjects and to study the metabolic effects of new therapies for the treatment of ADC in a clinical trial setting.

AIDS Dementia Complex↗
PubMed2003

k-Space based summary motion detection for functional magnetic resonance imaging.

Functional MRI studies are very sensitive to motion; head movements of as little as 1-mm translations or 1 degrees rotations may cause spurious signals. An algorithm was developed that uses k-space MRI data to monitor subject motion during functional MRI time series. A k-space weighted average of squared difference between the initial scan and subsequent scans is calculated, which summarizes subject motion in a single quality parameter; however, the quality parameter cannot be used for motion correction. The evolution of this quality parameter throughout a time series indicates whether head motion is within a predetermined limit. Fifty functional MRI studies were used to calibrate the sensitivity of the algorithm, using the six rigid-body registration parameters (three translations and three rotations) from the statistical parametric mapping (SPM99) package as a reference. The average correlation coefficient between the new quality parameter and the reference value from SPM was 0.84. The simple algorithm correctly classified acceptable or excessive motion with 90% accuracy, with the remaining 10% being borderline cases. This method makes it possible to evaluate brain motion within seconds after a scan and to decide whether a study needs to be repeated.

Algorithms↗
PubMed2003

Neuropsychological effects of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) in recreational users.

While neuropsychological studies on 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) users have been emerging, results have been inconsistent, possibly due to methodological issues. The current study examined the performance of 22 recreational MDMA users compared to 28 age, education, and IQ comparable normal control subjects on a comprehensive battery of neuropsychological tests. Results revealed no significant differences in cognitive functioning between the MDMA users and normal controls. However, greater use of MDMA was associated with poorer scores on several measures of nonverbal memory, and greater frequency users (> or = 50 times) evidenced significantly lower scores on 2 of 3 nonverbal memory tests compared to lesser frequency users (< 50 times). Our results suggest that a subgroup of MDMA patients, specifically heavy MDMA users, evidence declines in nonverbal (visual) memory, however, other cognitive areas appear to be spared.

Adult↗
PubMed2003

Magnetic resonance spectroscopy studies of GABA in neuropsychiatric disorders.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and is integral to managing brain excitability. GABA concentrations vary according to age, gender, and brain region. Magnetic resonance spectroscopy (MRS), with editing or with localized 2-dimensional chemical shift methods, can measure GABA levels in vivo, ex vivo, or in vitro, particularly at ultra-high magnetic field strengths. Proton ((1)H) MRS studies have found reduced or abnormal GABA concentrations in several neuropsychiatric disorders, including epilepsy, anxiety disorders, major depression, and drug addiction. Disorders with low GABA levels may be treated by augmentation of GABAergic function, such as by medications that block the degradation or reuptake of GABA. Examples of such a rational therapeutic approach include anticonvulsants that elevate brain GABA levels and are effective for the treatment of epilepsy and anxiety disorder.

Anxiety Disorders↗
PubMed2003

Persistent brain abnormalities in antiretroviral-naive HIV patients 3 months after HAART.

BACKGROUND: Proton magnetic resonance spectroscopy (1H-MRS) and neuropsychological tests may be useful for monitoring the effectiveness of highly active antiretroviral therapy (HAART) in HIV-associated brain injury. We aimed to evaluate whether brain abnormalities will improve 3 months after HAART. METHOD: Thirty-three HIV patients naive to antiretroviral medications were evaluated before and 3 months after HAART using 1H-MRS and neuropsychological tests; results were compared with those of 26 seronegative control subjects. RESULTS: Despite significant improvement in CD4 counts, and suppression of plasma and cerebrospinal fluid (CSF) viral loads, elevated brain metabolites (choline compounds and myoinositol in the frontal lobes) and neuropsychological tests abnormalities (including the computerized tests [CalCAP]) persisted after 3 months of HAART. In the basal ganglia, choline and myoinositol became elevated only after treatment. No interaction effect was observed between the number of CSF-penetrating drugs (one vs two) and changes (baseline vs 3 months) in any of the brain metabolites, cognitive performance or CSF viral load. CONCLUSIONS: The persistent brain abnormalities suggest ongoing repair or reactive inflammatory processes in the brain after 3 months of HAART. Regimens with two CSF-penetrating antiretroviral medications do not appear to be more effective than those with one CSF-penetrating drug in treating HIV brain injury at 3 months.

AIDS Dementia Complex↗
PubMed2002

The orbitofrontal cortex in methamphetamine addiction: involvement in fear.

We used Tellegen's Multidimensional Personality Questionnaire (MPQ) harm avoidance (fear) scale and the constraint superfactor as personality measures of inhibitory control and examined their association with glucose metabolism in the orbitofrontal gyrus at rest in 14 recently abstinent methamphetamine-dependent subjects and 22 comparison subjects. Higher MPQ scores were associated with higher relative orbitofrontal gyrus metabolism in the methamphetamine-dependent subjects. There was a tendency towards a negative association for the comparison subjects (test of coincidence of regression lines for the two subject groups: F = 3.3, df = 2,32; = 0.051). These results suggest that the role of the orbitofrontal cortex in inhibitory control can be manifested in stable personality predispositions and further implicate this region in the core characteristics of drug addiction.

Adult↗
PubMed2002

Perfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users.

This study aims to determine possible persistent abnormalities in regional cerebral blood flow (relative rCBF) and cognitive function in abstinent methamphetamine (METH) users. Twenty METH-dependent subjects (abstinent for 8+/-2 months) and 20 age- and gender-matched controls were evaluated with perfusion magnetic resonance imaging (pMRI) and neuropsychological tests. METH users showed decreased relative rCBF bilaterally in putamen/insular cortices (right: -12%; left: -10%) and the right lateral parietal brain region (-11%), but increased relative rCBF bilaterally in the left temporoparietal white matter (+13%), the left occipital brain region: (+10%) and the right posterior parietal region (+24%). Interaction effects were observed between METH and gender in the right occipital cortex and a midline brain region; female METH users showed increased relative rCBF (+15% both regions) whereas the male METH users had decreased relative rCBF (-10% and -18%, respectively). METH users performed within normal ranges on standard neuropsychological tests; however, they were slower on several tasks on the California Computerized Assessment Package (CalCAP), especially tasks that required working memory. These findings suggest that METH abuse is associated with persistent physiologic changes in the brain, and these changes are accompanied by slower reaction times on computerized measures of cognitive function.

Adult↗
PubMed2002

The effects of tamoxifen and estrogen on brain metabolism in elderly women.

BACKGROUND: Tamoxifen is used to treat breast cancer and may reduce the risk of breast cancer. However, there are conflicting reports as to whether tamoxifen use is associated with changes in brain metabolism and function or cognitive impairment. Consequently, we assessed the effects of tamoxifen and estrogen on the brain chemistry of elderly women. METHODS: We used proton magnetic resonance spectroscopy to measure the concentrations of N-acetyl-containing compounds, myo-inositol (MI), total creatine (creatine plus phosphocreatine), and choline-containing compounds in the frontal white matter, basal ganglia, and hippocampus of 76 elderly women of whom 16 had received tamoxifen therapy, 27 had received estrogen as hormone replacement therapy (HRT), and 33 had received neither (control group). A two-way analysis of variance (ANOVA) was performed to determine the statistical significance of differences in cerebral metabolite concentrations among subject groups and brain regions. All statistical tests were two-sided. RESULTS: Women in the tamoxifen and HRT groups had lower concentrations of MI in all areas than women in the control group (P =.02; overall group effect on ANOVA). Compared with the control group, the tamoxifen group (P =.004) and the HRT group (P =.06) had lower concentrations of MI in their basal ganglia. The MI concentration in the basal ganglia was inversely correlated with the duration of tamoxifen treatment (rho = -.72; P =.005). CONCLUSIONS: The reduced concentrations of MI in the brains of women treated with tamoxifen and HRT, compared with those of control women, suggest that tamoxifen has an effect similar to that of estrogen. These results, if confirmed, may alleviate concerns about the safety of using tamoxifen to reduce breast cancer risk in elderly women.

Aged↗
PubMed2002

Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naïve HIV patients.

This study aims to determine the relationship among cerebral metabolite concentrations (on proton magnetic resonance spectroscopy or (1)H MRS), cognitive function, and clinical variables (CD4, plasma and CSF viral loads, and lipids) in antiretroviral medication-nai;ve HIV patients. We hypothesized that the probable glial markers myo-inositol [MI] and choline compounds [CHO] would correlate with cognitive function, CD4 count, and viral loads, but not with serum lipids. Forty-five antiretroviral-drug-nai;ve HIV patients and 25 control subjects were evaluated. Frontal lobe [MI], [CHO], and total creatine [CR] were elevated, while basal ganglia [CR] were decreased, with increasing dementia severity. As a group, HIV patients showed slowing on fine motor (Grooved Pegboard) and psychomotor function (Trails A & B), and deficits on executive function (Stroop tasks). Lower CD4 counts and elevated plasma viral loads were associated with elevated frontal white matter [MI], which in turn correlated with the Stroop tasks. These findings suggest that systemic factors (resulting from suppressed immune function and higher plasma viral load) may lead to glial proliferation (elevated [MI], [CHO], and [CR]) in the frontal white matter, which in turn may contribute to deficits on executive function in HIV. Studying antiretroviral-nai;ve patients minimized the confounding effects of antiretroviral treatment on the clinical, MRS, and neuropsychological variables, and allowed for a more accurate assessment of the relationships among these measurements. Metabolite concentrations, rather than metabolite ratios, should be measured since [CR], a commonly used reference for metabolite ratios, varies with disease severity in both frontal lobe and basal ganglia.

AIDS Dementia Complex↗
PubMed2002

Treatment of hyperlipidemia.

In 1995 and 1996, US adults made more than 18 million office visits for the evaluation and treatment of hyperlipidemia, including 3.4% of all visits to family physicians. Among visits to family physicians, 4.1% included measurement of cholesterol levels.(1) Overall, mean cholesterol levels decreased from 220 in 1960-1962 to 203 in 1988-1994. During the same time period, the proportion of adults with elevated total cholesterol levels (> 240) decreased from 32% to 19%.(2) Despite this progress, the availability of more effective drugs, guidelines advocating increasingly aggressive treatment, and population-wide goals established in Healthy People 2010 will continue to increase the number of patients seen by family physicians for screening, diagnosis, and treatment of hyperlipidemia.

Adult↗