Biomedical subjects

Mark A Mintun

Publications and source records attributed to Mark A Mintun.

At least 19 recordsLinked to original sources

PubMed2007

Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults.

OBJECTIVES: To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals. DESIGN: Evaluation of CSF beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(42) and longitudinal clinical follow-up (from 1 to 8 years). SETTING: Longitudinal studies of healthy aging and dementia through an AD research center. PARTICIPANTS: Community-dwelling volunteers (n = 139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia. RESULTS: Individuals with very mild or mild AD have reduced mean levels of CSF Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(42) level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(42) ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0. CONCLUSIONS: The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Abeta(42), when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.

Aged↗

PubMed2006

Human brain glucose metabolism may evolve during activation: findings from a modified FDG PET paradigm.

In human brain, short-term physiological stimulation results in dramatic and proportional increase in blood flow and metabolic rate of glucose but minimal change in oxygen utilization, however, with continuing stimulation, we have observed that blood flow response diminishes and oxygen utilization increases. Given the temporal limitation of conventional methods to measure glucose metabolism in the human brain, we modified [(18)F]fluorodeoxyglucose (FDG) PET paradigm to evaluate the short-term and long-term effects of visual stimulation on human brain glucose metabolism. In the present study, seven healthy volunteers each underwent three dynamic FDG PET studies: at rest and after 1 min and 15 min of visual stimulation (using reversing black-white checkerboard) which continued for only 5 min after FDG injection. We found that increase in FDG uptake in the visual cortex was attenuated by 28% when preceded by 15 min of continuous visual stimulation (p<0.001). This decline in metabolism occurred in the absence of any behavior changes in task performance. The similarity in behavior of blood flow and glucose metabolism over time supports the hypothesis that, in activated brain, blood flow is modulated by changes in cytosolic free NADH/NAD(+) ratio related to increased glycolysis. Furthermore, the observed decline in glucose metabolism may reflect a shift from glycolytic to oxidative glucose metabolism with continued activation.

Adult↗

PubMed2006

Quantifying pulmonary inflammation in cystic fibrosis with positron emission tomography.

RATIONALE: Although infection contributes to morbidity in patients with cystic fibrosis (CF), the host inflammatory response is also an important cause of progressive pulmonary function deterioration. Quantifying the inflammatory burden in these patients is challenging and often requires invasive procedures. Positron emission tomographic imaging with [18F]fluorodeoxyglucose ([18FDG]) could be used as a noninvasive alternative to quantify lung inflammation. OBJECTIVE: To determine the relationships among lung [18F]FDG uptake, bronchoalveolar lavage (BAL) neutrophil concentrations, and pulmonary function in patients with CF. METHODS: Twenty patients and seven healthy volunteers were studied. A subset of seven patients also consented to undergo BAL. The uptake of [18F]FDG by the lungs was measured as the net influx rate constant Ki. Patients were stratified by rate of decline in pulmonary function into stable, intermediate, and rapidly declining groups. Ki was compared among groups and was correlated against neutrophil concentrations in BAL fluid. RESULTS: Ki was significantly elevated (p<0.05) among patients with CF as a whole compared with healthy control subjects (0.0015+/-0.0009 versus 0.0007+/-0.0002 ml blood/ml lung/min) but especially in patients with rapidly declining pulmonary function (0.0022+/-0.0011 ml blood/ml lung/min). Ki correlated positively with the number of neutrophils present in BAL fluid. CONCLUSION: Imaging with [18F]fluorodeoxyglucose and positron emission tomography can be used to assess inflammatory burden in patients with CF. Elevations in Ki may be able to identify patients with more aggressive disease and may be useful in monitoring changes in inflammatory burden in response to novel treatments.

Adult↗

PubMed2006

Antidepressant efficacy of olanzapine as monotherapy in major depressive disorder, without psychosis: a pilot study.

In this pilot study we assessed the efficacy of olanzapine as monotherapy in the treatment of major depressive disorder, without psychosis. We also demonstrated the in vivo 5-HT2A receptor occupancy of olanzapine using positron emission tomography. An open-label prospective 6-week study design with 14 patients who met the inclusion and exclusion criteria for the study were enrolled from the general community of the St. Louis metropolitan area. All patients met DSM-IV criteria for major depressive disorder without psychosis, had a Hamilton Depression Rating Scale (HAMD17) score >18 and were between the ages of 18 and 65. The primary measure of efficacy was the change in HAMD 17 total score from baseline to endpoint. The data were collected between 1998 and 2004. There was a significant reduction in the HAMD17 scores from baseline to endpoint. Half the patients (n=6) showed > or =50% reduction in their HAMD17 scores. This study points to the potential of olanzapine as a therapeutic agent for the treatment of major depressive disorder without psychosis.

Antidepressive Agents↗

PubMed2006

Cerebral blood flow changes during vagus nerve stimulation for depression.

Positron emission tomography (PET oxygen-15 labeled water or PET [15O]H2O) was used to identify changes in regional cerebral blood flow (rCBF) in response to acute vagus nerve stimulation (VNS) in four subjects with treatment-resistant major depression (TRMD). Four 90-s PET [15O]H2O scans were performed on each subject in an off-on sequence (2 VNS de-activated; 2 VNS activated). PET images were aligned, normalized for global uptake, and resampled to standard atlas space. Statistical t-images were used to evaluate change. VNS-induced increases in rCBF were found in the bilateral orbitofrontal cortex, bilateral anterior cingulate cortex, and right superior and medial frontal cortex. Decreases were found in the bilateral temporal cortex and right parietal area. Regions of change were consistent with brain structures associated with depression and the afferent pathways of the vagus nerve.

Adult↗

PubMed2006

Regulation of blood flow in activated human brain by cytosolic NADH/NAD+ ratio.

It has been known for more than a century that increases in neuronal activity in the brain are reliably accompanied by changes in local blood flow. More recently it has been appreciated that these blood flow increases are accompanied by increases in glycolysis that are much greater than the increases in oxidative phosphorylation. It has been proposed by us and others that this activity-induced increase in glycolysis mediates the increase in blood flow by mechanisms linked through the near-equilibrium relationship between cytosolic NADH/NAD+ and the lactate/pyruvate ratios. Here we show in awake human subjects that by transiently raising blood pyruvate concentration during local increases in functional brain activity, a maneuver designed to reduce the cytosolic NADH/NAD+ ratio, the expected blood flow response measured with positron-emission tomography is significantly attenuated. This result provides critical additional support for the hypothesis that, like in anesthetized rodents, the cytosolic NADH/NAD+ ratio of awake human subjects links activity-induced increases in glycolysis to signaling pathways for the regulation of blood flow.

Adult↗

PubMed2006

FDG-PET imaging of pulmonary inflammation in healthy volunteers after airway instillation of endotoxin.

Recent studies indicate that a focal, limited, inflammatory response can be safely elicited after direct bronchial instillation of small doses of endotoxin into a single lung segment. Because the radiotracer [18F]fluorodeoxyglucose ([18F]FDG) is taken up at accelerated rates within inflamed tissues, we hypothesized that we could detect and quantify this regional inflammatory response with positron emission tomography (PET). We imaged 18 normal volunteers in a dose-escalation study with 3 endotoxin dosing groups (n = 6 in each group): 1 ng/kg, 2 ng/kg, and 4 ng/kg. Endotoxin was instilled by bronchoscopy into a segment of the right middle lobe, with imaging performed approximately 24 h later, followed by bronchoalveolar lavage (BAL). A "subtraction imaging analysis" was performed in the highest dose cohort to identify the area of inflammation, using the preendotoxin scan as a baseline. BAL neutrophil counts were significantly higher in the highest dose group compared with the other two groups (1,413 +/- 625 vs. 511 +/- 396 and 395 +/- 400 cells/mm3; P < 0.05). Autoradiography performed on cells harvested by BAL showed specific [3H]deoxyglucose ([3H]DG) uptake limited to neutrophils. In vitro [3H]DG uptake in BAL neutrophils in the 4 ng/kg dose group (but not in the 2 ng/kg group) was statistically greater than in peripheral blood neutrophils obtained before endotoxin instillation. The rate of [18F]FDG uptake was greatest in the 4 ng/kg group, with a consistent, statistically significant increase in the rate of uptake after endotoxin instillation compared with baseline. We conclude that the inflammatory response to low-dose endotoxin in a single lung segment can be visualized and quantified by imaging with FDG-PET.

Autoradiography↗

PubMed2006

Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans.

OBJECTIVES: Amyloid-beta(42) (Abeta(42)) appears central to Alzheimer's disease (AD) pathogenesis and is a major component of amyloid plaques. Mean cerebrospinal fluid (CSF) Abeta(42) is decreased in dementia of the Alzheimer's type. This decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. We investigated this hypothesis. METHODS: We compared the in vivo brain amyloid load (via positron emission tomography imaging of the amyloid-binding agent, Pittsburgh Compound-B [PIB]) with CSF Abeta(42) and other measures (via enzyme-linked immunosorbent assay) in clinically characterized research subjects. RESULTS: Subjects fell into two nonoverlapping groups: those with positive PIB binding had the lowest CSF Abeta(42) level, and those with negative PIB binding had the highest CSF Abeta(42) level. No relation was observed between PIB binding and CSF Abeta(40), tau, phospho-tau(181), plasma Abeta(40), or plasma Abeta(42). Importantly, PIB binding and CSF Abeta(42) did not consistently correspond with clinical diagnosis; three cognitively normal subjects were PIB-positive with low CSF Abeta(42), suggesting the presence of amyloid in the absence of cognitive impairment (ie, preclinical AD). INTERPRETATION: These observations suggest that brain amyloid deposition results in low CSF Abeta(42), and that amyloid imaging and CSF Abeta(42) may potentially serve as antecedent biomarkers of (preclinical) AD.

Aged↗

PubMed2006

Brain work and brain imaging.

Functional brain imaging with positron emission tomography and magnetic resonance imaging has been used extensively to map regional changes in brain activity. The signal used by both techniques is based on changes in local circulation and metabolism (brain work). Our understanding of the cell biology of these changes has progressed greatly in the past decade. New insights have emerged on the role of astrocytes in signal transduction as has an appreciation of the unique contribution of aerobic glycolysis to brain energy metabolism. Likewise our understanding of the neurophysiologic processes responsible for imaging signals has progressed from an assumption that spiking activity (output) of neurons is most relevant to one focused on their input. Finally, neuroimaging, with its unique metabolic perspective, has alerted us to the ongoing and costly intrinsic activity within brain systems that most likely represents the largest fraction of the brain's functional activity.

Animals↗

PubMed2005

Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory.

Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

Adolescent↗

PubMed2005

Utilizing advanced imaging and surrogate markers across the spectrum of Alzheimer's disease.

Alzheimer's disease is a degenerative neurological condition characterized by the presence of beta-amyloid plaques and neurofibrillary tangles in the limbic and neocortical regions of the brain. Pittsburgh Compound-B (PIB), a benzothiazole analog, has recently been found to specifically label amyloid deposits in positron emission tomography (PET) studies of the brain, opening the door for a wide range of applications related to Alzheimer's disease. In this article, data demonstrating the specificity of PIB as a PET tracer for beta-amyloid lesions are reviewed, and the potential clinical applications of PIB PET imaging is discussed. Because amyloid plaques are common even in elderly individuals who are not suffering from dementia, the primary diagnostic function of PIB PET imaging presumably would be to rule out, rather than definitively confirm, Alzheimer's diagnoses in elderly patients. Other possible uses include monitoring plaque loads in patients receiving anti-amyloid therapy for Alzheimer's disease, as well as assessing plaque formation in unaffected individuals as a means of evaluating future Alzheimer's disease.

Aged↗

PubMed2004

Positron emission tomography in limited-stage small-cell lung cancer: a prospective study.

PURPOSE: To determine how often positron emission tomography with [(18)F]fluoro-2-deoxy-D-glucose (FDG-PET) detects extensive-stage small-cell lung cancer (SCLC) in patients considered to have limited-stage disease based on conventional staging procedures, and to determine the impact of PET on treatment planning for presumed limited-stage SCLC. PATIENTS AND METHODS: We prospectively performed pretreatment FDG-PET on 24 patients determined by conventional staging methods to have limited-stage SCLC (defined as disease that could be encompassed within a reasonable radiotherapy portal, excluding bilateral supraclavicular disease). PET images were evaluated for evidence of extensive-stage disease. Tumor-node-metastasis system staging was also assigned for each patient, with and without PET information. RESULTS: FDG-PET demonstrated findings consistent with extensive-stage SCLC in three of 24 patients. FDG-PET correctly upstaged two (8.3%) of 24 patients to extensive-stage disease (95% CI, 1.03% to 27.0%). PET correctly identified tumor in each SCLC mass (primary or nodal) that was suspected on computed tomography (CT) imaging, thus giving a lesion-based sensitivity relative to CT of 100%. PET identified unsuspected regional nodal metastasis in six (25%) of 24 patients, and the radiation therapy plan was significantly altered to include the PET-positive/CT-negative nodes within the high-dose region in each of these patients. Brain PET images in 23 patients disclosed no evidence of brain metastasis. CONCLUSION: FDG-PET has high sensitivity for SCLC and appears to be of value for initial staging and treatment planning of patients with presumed limited-stage disease.

Adult↗

PubMed2004

Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography.

BACKGROUND: Serotonin 5-HT(2A) receptors play an important role in the regulation of many functions that are disturbed in patients with major depressive disorder. Postmortem and positron emission tomography studies have reported both increased and decreased 5-HT(2A) receptor binding in different limbic and paralimbic regions. METHODS: We conducted a quantitative 5-HT(2A) receptor binding study using positron emission tomography and [(18)F]altanserin of four regions hypothesized to have altered levels of 5-HT(2A) receptors in major depressive disorder. Using a four-compartment model, the 5-HT(2A) receptor distribution was estimated by calculating the regional [(18)F]altanserin k(3)/k(4) ratio in which k(3) is the rate of binding to the receptor and k(4) is the rate of dissociation from the receptor. Forty-six antidepressant-free patients with major depressive disorder and 29 healthy control subjects were enrolled. RESULTS: 5-HT(2A) receptor binding in the hippocampus was reduced by 29% in depressed subjects (p =.004). In other regions, 5-HT(2A) receptor binding was decreased (averaging 15%) but not significantly. Both groups had similar age-dependent decreases in 5-HT(2A) receptors throughout all brain regions. CONCLUSIONS: Altered serotoninergic function in the hippocampus is likely involved in the disturbances of mood regulation in major depressive disorder, although the specific role of the 5-HT(2A) receptor changes is still unclear.

Adult↗

PubMed2004

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain.

The factors regulating cerebral blood flow (CBF) changes in physiological activation remain the subject of great interest and debate. Recent experimental studies suggest that an increase in cytosolic NADH mediates increased blood flow in the working brain. Lactate injection should elevate NADH levels by increasing the lactate/pyruvate ratio, which is in near equilibrium with the NADH/NAD(+) ratio. We studied CBF responses to bolus lactate injection at rest and in visual stimulation by using positron-emission tomography in seven healthy volunteers. Bolus lactate injection augmented the CBF response to visual stimulation by 38-53% in regions of the visual cortex but had no effect on the resting CBF or the whole-brain CBF. These lactate-induced CBF increases correlated with elevations in plasma lactate/pyruvate ratios and in plasma lactate levels but not with plasma pyruvate levels. Our observations support the hypothesis that an increase in the NADH/NAD(+) ratio activates signaling pathways to selectively increase CBF in the physiologically stimulated brain regions.

Adult↗

PubMed2004

Decreased hippocampal 5-HT(2A) receptor binding in older depressed patients using [18F]altanserin positron emission tomography.

Serotonin receptor changes have been associated with the pathophysiology and treatment of major depression. Only one other study has investigated serotonin receptor changes in older depressed patients. We used positron emission tomography (PET) and [18F]altanserin, a ligand with high affinity for the 5-HT(2A) receptor, to examine the relationship between 5-HT(2A) receptor density and depression. Depressed subjects (n = 16), age > 50 years, were recruited as part of a larger study. Older depressed subjects consisted of early-onset recurrent depression (EORD, n = 11) and late-onset depression (LOD, n = 5). An age-matched control group (n = 9) was also recruited. All subjects were right-handed, nonsmokers and antidepressant-free. Regions of interest were determined on a summed MPRAGE scan transformed into Talairach space and coregistered with the PET images. Depressed subjects had less hippocampal 5-HT(2A) receptor binding than controls (p = 0.05). No significant differences in receptor binding were found between EORD and LOD subjects. Depressed subjects not previously treated for depression (n = 6) had less hippocampal 5-HT(2A) receptor binding (p = 0.04) than previously treated subjects (n = 10). It may be that prior medication treatment provides a compensatory upregulation of the 5-HT(2A) receptor.

Aged↗

PubMed2004

Cerebral perfusion response to successful treatment of depression with different serotoninergic agents.

In 19 patients with major depressive disorder, effective treatment with selective serotonin reuptake inhibitors (SSRIs) or amesergide (AMSG) was associated with increased cerebral perfusion in anterior cingulate cortex (SSRI and AMSG) and in medial prefrontal cortex (AMSG). Both selective serotonin reuptake inhibitors and AMSG exert antidepressant action through the serotonin (5-HT) system as reuptake inhibitors. Amesergide differs from SSRIs in that it is also a highly selective 5-HT antagonist, which may in part account for differences in cerebral blood flow response to treatment.

Adult↗

PubMed2004

Quantitation of pulmonary transgene expression with PET imaging.

UNLABELLED: PET imaging represents a promising approach for noninvasive monitoring of reporter gene expression in living subjects. We evaluated the relationship between various methods of quantifying the imaging signal and in vitro assays of the expression of a PET reporter gene (a mutant Herpes simplex virus-1 thymidine kinase (mHSV1-tk); 9-(4-(18)F-fluoro-3-hydroxymethylbutyl)guanine ((18)F-FHBG) was used as the PET reporter probe. METHODS: In 14 rats, pulmonary gene transfer was performed by intratracheal administration of various amounts of an adenovector containing a fusion gene encoding for mHSV1-tk and an enhanced green fluorescent protein. Three days later, the animals were divided into 2 groups. One group (n = 7) did not receive any other interventions. The other group was treated with alpha-naphthylthiourea (ANTU) to increase pulmonary vascular permeability. All rats were injected intravenously with (18)F-FHBG. Two additional rats in both groups received a null adenovector and served as controls. In the normal rats, repetitive blood samples were obtained and PET imaging was performed simultaneously using a dynamic imaging protocol. Rate constants estimating (18)F-FHBG transport (K(1)) or trapping (k(3)) within target cells were generated by compartmental modeling. After euthanasia, pulmonary uptake of (18)F-FHBG was determined using a gamma-counter in all rats, and in vitro assays of transgene expression were performed on lung tissue. RESULTS: In normal rats, pulmonary uptake of (18)F-FHBG increased as thymidine kinase (TK) activity increased only at low levels of mHSV1-tk expression and then plateaued as TK activity continued to increase. Compartmental modeling failed to improve the correlation with in vitro assays of transgene expression. However, a linear relationship was obtained between the pulmonary uptake of (18)F-FHBG and in vitro assays of TK activity in rats treated with ANTU. CONCLUSION: In rodent lungs, (18)F-FHBG uptake appears to be a function of both transport into tissues expressing the transgene as well as the level of transgene expression itself.

Animals↗

PubMed2004

Comparison of methods to quantitate 18F-FDG uptake with PET during experimental acute lung injury.

UNLABELLED: PET with 18F-FDG may be useful for quantifying neutrophilic activation. We previously demonstrated that pulmonary neutrophil sequestration could be detected during acute lung injury (ALI), even without migration into the alveolar compartment. Using the influx constant Ki as the method to quantify lung 18F-FDG uptake, we also showed that Ki correlated positively with in vitro assays of 3H-deoxyglucose (3H-DG) uptake in cells harvested via bronchoalveolar lavage. In the present study, we have reanalyzed data from that study to determine if simpler nonkinetic methods of quantifying the pulmonary uptake of 18F-FDG could be as powerful as calculating Ki. METHODS: 18F-FDG uptake was quantified as Ki, calculated by 3-compartmental model analysis (used as the gold standard) and Patlak graphical analysis, with and without normalization for initial volume of tracer distribution; the standardized uptake value; and the tissue-to-plasma activity ratio (TPR). RESULTS: Values for Ki, determined either from a 3-compartmental model analysis of the time-activity data or by Patlak graphical analysis, were highly correlated (R2 = 0.97). The correlation was worse if these variables were normalized for the initial volume of tracer distribution. TPR was highly correlated with Ki determined by the compartmental model (R2 = 0.96) and with in vitro measurements of 3H-DG uptake (R2 = 0.63). CONCLUSION: The TPR is a simple and equally effective alternative to dynamic imaging in determining net 18F-FDG uptake during ALI. Normalization of the kinetic data for differences in the initial volume of tracer distribution does not contribute significantly to signal interpretation during ALI.

Animals↗