The neurobiology of attention-deficit/hyperactivity disorder.
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Animals↗
Biomedical subjects
Alan J Fischman
Publications and source records attributed to Alan J Fischman.
In vivo neuroreceptor imaging in attention-deficit/hyperactivity disorder: a focus on the dopamine transporter.
There is converging evidence of the role of catecholamine dysregulation in the underlying pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent genetic, treatment, and imaging studies have highlighted the role of DAT in ADHD. There is an emerging literature on in vivo neuroreceptor imaging of DAT in ADHD and control subjects reported by a number of groups internationally. A comprehensive review of existing imaging studies of DAT binding in ADHD shows that six of eight independent studies by six different groups have reported increased DAT binding in (mostly) treatment-naïve children and adults with ADHD. Although there is fair agreement regarding the presence and direction of abnormal DAT binding, there remains disagreement as to the magnitude of the finding and the importance of many potentially confounding variables, including clinical characteristics and imaging methodology. Three studies by three different groups have reported decreased DAT binding after methylphenidate treatment. Interpretation of the latter finding awaits clarification of the issue of timing of drug administration and imaging to disentangle receptor occupancy from downregulation.
Age Factors↗
High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease.
OBJECTIVES: We investigated the acute effect of orally administered high-dose folic acid on coronary dilator function in humans. BACKGROUND: Folic acid and its active metabolite, 5-methyltetrahydrofolate, increase endothelium-dependent vasodilation in human peripheral circulation. However, the acute effect on coronary circulation is not known. METHODS: Fourteen patients with ischemic heart disease, age 62 +/- 12 years (mean +/- SD), were enrolled in a double-blind, placebo-controlled crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) were determined by positron emission tomography, and myocardial flow reserve was calculated. Each patient was studied after ingestion of placebo and after ingestion of 30 mg folic acid. Myocardial zones were prospectively defined physiologically as "normal" versus "abnormal" on the basis of MBF response to adenosine 140 microg/kg/min (normal = MBF >1.65 ml/min/g). Abnormal and normal zones were analyzed separately in a patient-based analysis. RESULTS: Folate was associated with a reduction in mean arterial pressure (100 +/- 12 mm Hg vs. 96 +/- 11 mm Hg, placebo vs. folate, p < 0.03). Despite the fall in mean arterial pressure, folic acid significantly increased the MBF dose response to adenosine (p < 0.001 using analysis of variance) in abnormal zones, whereas MBF in normal zones did not change. In abnormal segments, folic acid increased peak MBF by 49% (1.45 +/- 0.59 ml/min/g vs. 2.16 +/- 1.01 ml/min/g, p < 0.02). Furthermore, folate increased dilator reserve by 83% in abnormal segments (0.77 +/- 0.59 vs. ml/min/g 1.41 +/- 1.08 ml/min/g, placebo vs. folate, p < 0.05), whereas dilator reserve in normal segments remained unchanged (2.00 +/- 0.61 ml/min/g vs. 2.12 +/- 0.69 ml/min/g, placebo vs. folate, p = NS). CONCLUSIONS: The data demonstrate that high-dose oral folate acutely lowers blood pressure and enhances coronary dilation in patients with coronary artery disease.
Adenosine↗
Self-organized patchiness in asthma as a prelude to catastrophic shifts.
Asthma is a common disease affecting an increasing number of children throughout the world. In asthma, pulmonary airways narrow in response to contraction of surrounding smooth muscle. The precise nature of functional changes during an acute asthma attack is unclear. The tree structure of the pulmonary airways has been linked to complex behaviour in sudden airway narrowing and avalanche-like reopening. Here we present experimental evidence that bronchoconstriction leads to patchiness in lung ventilation, as well as a computational model that provides interpretation of the experimental data. Using positron emission tomography, we observe that bronchoconstricted asthmatics develop regions of poorly ventilated lung. Using the computational model we show that, even for uniform smooth muscle activation of a symmetric bronchial tree, the presence of minimal heterogeneity breaks the symmetry and leads to large clusters of poorly ventilated lung units. These clusters are generated by interaction of short- and long-range feedback mechanisms, which lead to catastrophic shifts similar to those linked to self-organized patchiness in nature. This work might have implications for the treatment of asthma, and might provide a model for studying diseases of other distributed organs.
Asthma↗
Using imaging biomarkers to accelerate drug development and clinical trials.
There is increasing evidence that human medical imaging can help answer key questions that arise during the drug development process. Imaging modalities such as magnetic resonance imaging, computed tomography and positron emission tomography can offer significant insights into the bioactivity, pharmacokinetics and dosing of drugs, in addition to supporting registration applications. In this review, examples from oncology, neurology, psychiatry, infectious diseases and inflammatory diseases are used to illustrate the role imaging can play. We conclude with some remarks concerning new developments that will be required to significantly advance the field of pharmaco-imaging.
Animals↗
The dopamine transporter and attention-deficit/hyperactivity disorder.
The high incidence of attention-deficit/hyperactivity disorder (ADHD) and escalating use of ADHD medications present a compelling case for clarifying the pathophysiology of, and developing laboratory or radiologic tests for, ADHD. Currently, the majority of specific genes implicated in ADHD encode components of catecholamine signaling systems. Of these, the dopamine transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate); the DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Medications for ADHD interfere with dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular dopamine levels in DAT-rich brain regions. In brain regions expressing both the DAT and the norepinephrine transporter (NET), the relative contributions of dopamine and norepinephrine to ADHD pathophysiology and therapeutic response are obfuscated by the capacity of the NET to clear dopamine as well as norepinephrine. Thus, ADHD medications targeting DAT or NET might disperse dopamine widely and consign dopamine storage and release to regulation by noradrenergic, as well as dopaminergic neurons.
Adaptation, Physiological↗
A new approach for sequencing human IRS1 phosphotyrosine-containing peptides using CapLC-Q-TOF(micro).
Reversible phosphorylation of proteins functions as a biological switching network for activation and inhibition of downstream biological processes. Since phosphorylations of these sites are often transient processes, and hence sub-stoichiometric, systematic characterization of phosphorylation sites is a formidable challenge. In this work, a new approach was developed to pinpoint phosphotyrosine sites on tyrosine-containing peptides. This required (1) the development of a new and highly sensitive nano-electrospray assembly and (2) validation of the concept that the specificity and detection limit for trace levels of phosphotyrosine immonium ion in peptide mixtures from protein digests can be increased by varying the collision energy. With our method, an automatic tandem mass spectrometric analysis of peptides eluted from a C(18) capillary liquid chromatographic column is triggered by a positive confirmation of phosphotyrosine immonium ion in a time-of-flight mass spectrometric survey. The approach was tested by analyzing the phosphorylation of human IRS-1 peptides that interact with the Src-homology 2 domain and mixtures of these peptides with tryptic digests of bovine serum albumin and horse heart myoglobin.
Humans↗
Site-specific detection of S-nitrosylated PKB alpha/Akt1 from rat soleus muscle using CapLC-Q-TOF(micro) mass spectrometry.
Protein Kinase Balpha(PKBalpha, or Akt1) is believed to play a crucial role in programmed cell death, cancer progression and the insulin-signaling cascade. The protein is activated by phosphorylation at multiple sites and subsequently phosphorylates and activates eNOS. Free cysteine residues of the protein may capture reactive, endogenously produced nitric oxide (NO) as S-nitrosothiols. Site-specific detection of S-nitrosylated cysteine residues, usually at low stoichiometry, has been a major challenge in proteomic research largely due to the lack of mass marker for S-nitrosothiols that are very labile under physiologic conditions. In this report we describe a sensitive and specific MS method for detection of S-nitrosothiols in PKB alpha/Akt1 in rat soleus muscle. PKB alpha/Akt1 was isolated by immunoprecipitation and 2D-gel electrophoresis, subjected to in-gel tryptic digestion, and cysteinyl nitrosothiols were reacted with iodoacetic acids [2-C(12)/C(13) = 50/50] under ascorbate reduction conditions. This resulted in the production of relatively stable carboxymethylcysteine (CMC) immonium ions (m/z 134.019 and m/z 135.019) within a narrow argon collision energy (CE = 30 +/- 5 V) in the high MS noise region. In addition, free and disulfide-linked cysteine residues were converted to carboxyamidomethylcysteines (CAM). Tryptic S-nitrosylated parent ion was detected with a mass accuracy of 50 mDa for the two CMC immonium ions at the triggered elution time during capillary liquid chromatography (LC) separation. A peptide containing Cys(296) was discriminated from four co-eluting tryptic peptides under lock mass conditions (m/z 785.8426). S-nitrosothiol in the tryptic peptide, ITDFGLBKEGIK (B: CAM, [M + 2H](2+) = 690.86, Found: 690.83), is believed to be present at a very low level, since the threshold for the CMC immonium trigger ions was set at 3 counts/s in the MS survey. The high levels of NO that are produced under stress conditions may result in increased S-nitrosylation of Cys(296) which blocks disulfide bond formation between Cys(296) and Cys(310) and suppresses the biological effects of PKB alpha/Akt1. With the procedures developed here, this process can be studied under physiological and pathological conditions.
Animals↗
Detection of liver metastases from gastrointestinal cancer: comparision of high resolution MnDPDP enhanced MRI and FDG-PET.
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Adenocarcinoma↗
Role of [18F]-dopa-PET imaging in assessing movement disorders.
FD-PET has proved to be an extremely useful technique for the noninvasive evaluation of nigrostriatal pathophysiology in patients with PD and other movement disorders. The development of ratio methods for image analysis has greatly reduced the complexity of these PET studies and has facilitated data analysis. With the recent advances in cyclotron targetry and automated synthesis modules FD-PET will soon become an important component of the clinical armamentarium.
Dihydroxyphenylalanine↗
Effects of sildenafil on myocardial blood flow in humans with ischemic heart disease.
BACKGROUND: We tested the hypothesis that sildenafil increases myocardial dilator reserve in humans with ischemic heart disease. METHODS: Positron emission tomography measured myocardial blood flow in 14 patients with ischemic heart disease. Patients were studied twice, in double-blind, placebo-control, cross-over design with sildenafil (or placebo) given approximately 2-3 h before measurements of hemodynamics and myocardial blood flow: at rest, with cold pressor stress and with adenosine. All myocardial segments of each patient with myocardial blood flow <1.65 ml/min per g with adenosine under placebo conditions were combined into one abnormal zone for that patient. Segments with myocardial blood flow >1.65 ml/min per g were averaged and combined into a normal zone for that patient. RESULTS: At rest, rate pressure product (heart rate x systolic arterial pressure, mmHg/min) was comparable, as was abnormal zone myocardial blood flow (ml/min per g; 0.76+/-0.48 placebo versus 0.64+/-0.20 sildenafil, both P=NS; mean+/-SD). Both rate pressure product and myocardial blood flow increased (P<0.01) with cold pressor stress (11+/-3 K and 1.14+/-0.59 placebo versus 10+/-3 K and 1.21+/-0.62 sildenafil). However, sildenafil failed to improve the myocardial blood flow response to cold pressor stress in abnormal or normal zones. In contrast, abnormal zone myocardial blood flow reserve with adenosine and sildenafil (2.6+/-0.7) exceeded that with adenosine and placebo (2.0+/-1.3, P<0.04, paired sign test). CONCLUSION: Sildenafil improves myocardial blood flow dilator response to adenosine in abnormal zones, possibly by augmenting nitric oxide-mediated increases in cGMP because adenosine response in part is nitric oxide dependent. Failure to improve myocardial blood flow response to cold pressor stress suggests that alpha-adrenergic constriction may offset enhanced nitric oxide effects. Clinically, the data suggest sildenafil may exert an anti-ischemic effect in patients with coronary artery disease.
Adult↗
Comparison of alignment of computer-registered data sets: combined PET/CT versus independent PET and CT of the thorax.
PURPOSE: To retrospectively determine whether alignment of registered positron emission tomographic (PET) and computed tomographic (CT) data sets obtained independently varies significantly from alignment of data sets acquired from a combined PET/CT scanner. MATERIALS AND METHODS: The study was approved by the institution's Human Research Committee with a waiver of informed consent and complied with HIPAA. Whole-body combined PET/CT data sets and separate routinely positioned thoracic CT data sets were obtained from 12 patients (six men, six women; mean age, 48.6 years; range, 24-62 years). Separate PET and thoracic CT data sets matched for patient positioning and respiration were acquired on the same day for nine patients (four men, five women; mean age, 71 years; range, 51-90 years). Computer nonlinear registration was performed on PET and CT data sets from combined PET/CT (fusion group 1), PET data sets from combined PET/CT with unmatched thoracic CT (fusion group 2), and data sets from separate PET and CT matched for patient positioning and respiration (fusion group 3). Quality of alignment was assessed by two radiologists in consensus blinded to the source of registered data in each fusion group at the following anatomic locations: diaphragm, aortic arch, heart, thoracic spine, and lung apices. Results were compared by using the Wilcoxon paired signed rank and unpaired rank sum tests. RESULTS: Quality of alignment did not significantly differ between fusion group 1 and fusion group 3. Fusion group 1 provided significantly better alignment in two of five anatomic locations (P = .008 for diaphragm and P = .031 for heart) than fusion group 2. Fusion group 3 provided significantly better alignment in two of five anatomic locations (P = .037 for diaphragm and P = .009 for heart) than fusion group 2. CONCLUSION: Thoracic anatomic alignment does not significantly differ between registered PET and CT data sets acquired on a combined PET/CT scanner or from separate PET and CT scanners obtained on the same day when carefully matched for anatomic positioning and respiration.
Adult↗
Lipomatous hypertrophy of the interatrial septum: prevalence and features on fusion 18F fluorodeoxyglucose positron emission tomography/CT.
OBJECTIVE: To determine the prevalence of lipomatous hypertrophy of the interatrial septum (LHIS) on CT and its metabolic pattern on 18F fluorodeoxyglucose (FDG)-positron emission tomography (PET). METHOD AND MATERIALS: Eight hundred two CT PET scans were reviewed. Patients were included if the interatrial septum was > or = 1 cm and excluded if there was evidence of malignancy in the adjacent lung, hilum, or mediastinum. CT scans were fused with PET scans, and the mean standardized uptake value (SUV) was calculated over the LHIS, chest wall (CW) fat, and mediastinal blood pool. CT scans were reviewed for presence of excessive fat in the mediastinum, pericardial, peridiaphragmatic, peritoneal, and retroperitoneal regions and for the presence of emphysema. Medical records were reviewed for body mass index (BMI) and history of arrhythmia. RESULTS: Twenty-three of 802 patients (2.8%) had LHIS on CT (9 women and 14 men); average age was 75.6 years (range, 58 to 95 years). Average BMI of 17 patients (+/- SD) was 31 +/- 4.9 (range, 22.1 to 39.9). Mean CT values were as follows: thickening of LHIS, 1.47 +/- 0.35 cm (range, 1.07 to 2.25 cm); LHIS, - 79.6 + 24.5 Hounsfield unit (HU) [range, - 11 to - 121 HU]. LHIS was dumbbell shaped in 18 patients. Mean SUVs were as follows: LHIS, 1.84 +/- 0.10 (range, 0.48 to 3.48); CW fat, 0.36 + 0.37 (range, 0.04 to 1.98); blood pool, 1.74 + 0.51 (range, 0.25 to 2.71). The SUV of LHIS was greater than the SUV of CW wall fat in all patients (p < 0.0001). There was significant correlation between SUV and thickness of the LHIS on CT (p < 0.0001, r = 0.883). Those with dumbbell-shaped LHIS (p < 0.003) and presence of emphysema (p < 0.0377) had greater LHIS mean SUV. CONCLUSION: The SUV of LHIS was greater than the SUV of CW fat in all patients. LHIS with greater thickness or dumbbell shape had greater FDG uptake. These findings on CT and PET are important to recognize in order to avoid false-positive FDG-PET interpretations.
Aged↗
Lipomatous hypertrophy of the interatrial septum: increased uptake on FDG PET.
OBJECTIVE: The objective of our study was to evaluate FDG uptake in patients with cardiac lipomatous hypertrophy of the interatrial septum (LHIS). CONCLUSION: Increased FDG uptake occurs in LHIS, a benign fatty infiltration of the interatrial septum. Increased uptake in the right heart on FDG PET warrants correlation with additional imaging to assess for LHIS and avoid false interpretation of malignancy.
Aged↗
Detection of liver metastases from adenocarcinoma of the colon and pancreas: comparison of mangafodipir trisodium-enhanced liver MRI and whole-body FDG PET.
OBJECTIVE: The objective of our study was to assess the relative performance of mangafodipir trisodium-enhanced liver MRI and whole-body FDG PET for the detection of liver metastases from adenocarcinoma of the colon and pancreas. MATERIALS AND METHODS: Imaging data of 34 patients (23 men, 11 women; age range, 44-78 years) with adenocarcinoma of the colon (n = 27) or adenocarcinoma of the pancreas (n = 7) who had undergone mangafodipir trisodium-enhanced liver MRI and whole-body FDG PET were retrospectively reviewed for the presence and number of liver metastases. Histopathology (n = 25) or follow-up imaging (n = 9) served as the standard of reference. Breath-hold T1-weighted gradient-recalled echo, respiratory-triggered T2-weighted fast spin-echo, and mangafodipir trisodium-enhanced axial fat-saturated high-spatial-resolution (256 x 512) T1-weighted gradient-recalled echo images were obtained on a 1.5-T scanner. FDG PET was performed after the injection of 15-20 mCi (555-740 MBq) of FDG. The sensitivity, positive predictive value, and accuracy were calculated for each technique. The performances of the two techniques were compared using the Fisher's exact test. RESULTS: Thirty patients had hepatic metastases and four had no hepatic metastases according to the standard of reference. The total number of metastases was 79, including 33 that measured less than 1 cm. Based on a per-patient analysis, MRI and FDG PET showed sensitivities of 96.6% and 93.3%, positive predictive values of 100% and 90.3%, and accuracies of 97.1% and 85.3%, respectively. According to a per-lesion analysis, MRI and FDG PET showed sensitivities of 81.4% and 67.0%, positive predictive values of 89.8% and 81.3%, and accuracies of 75.5% and 64.1%, respectively. MRI detected more hepatic metastases than FDG PET (p = 0.016). Of the 33 subcentimeter lesions confirmed on the standard of reference, all were identified on MRI, whereas only 12 were detected on FDG PET (p = 0.0001). CONCLUSION: In patients with colon and pancreatic adenocarcinoma, high-spatial-resolution mangafodipir trisodium-enhanced liver MRI and whole-body FDG PET were comparable in the detection of patients with liver metastases. FDG PET provided additional information about extrahepatic disease and was useful in initial staging. However, significantly more and smaller liver metastases were detected on MRI than on FDG PET.
Adenocarcinoma↗
Evaluation of trans-9-18F-fluoro-3,4-Methyleneheptadecanoic acid as a PET tracer for myocardial fatty acid imaging.
UNLABELLED: This study describes the radiosynthesis and preliminary biologic evaluation of trans-9(RS)-(18)F-fluoro-3,4(RS,RS)-methyleneheptadecanoic acid ((18)F-FCPHA) as a new potential probe for assessing myocardial fatty acid metabolism by PET. This fatty acid, containing a cyclopropyl moiety in the beta,gamma-position, was designed to enter the myocardium by the same mechanism as natural fatty acids and to undergo partial metabolism before being trapped in the cell. METHODS: (18)F-FCPHA and the beta-methyl analog 8(RS)-(18)F-fluoro-3(RS)-methylheptadecanoic acid ((18)F-FBMHA) were prepared from their corresponding mesylate precursors by nucleophilic substitution. The precursors used for labeling were fully characterized, and the data were consistent with the proposed structures. Biodistribution studies of each tracer were performed with Sprague-Dawley rats at 5 and 60 min after injection. Sequential imaging of a rhesus monkey injected with 222 MBq of (18)F-FCPHA was performed by use of a microPET camera. RESULTS: At 5 and 60 min, heart uptake values measured as mean +/- SD percentage injected dose per gram (%ID/g) in rats for (18)F-FCPHA were 1.55 +/- 0.72 and 1.43 +/- 0.14, respectively. The heart-to-blood ratios at 5 and 60 min, an indication of target definition, were 25.8 and 20.4, respectively. The heart-to-lung ratios at 5 and 60 min were 3.3 and 4.6, respectively. Bone accumulation (%ID/g), an indication of defluorination, was 0.16 +/- 0.03 at 5 min and increased to 0.70 +/- 0.39 at 60 min. The heart-to-blood ratio obtained with (18)F-FBMHA was 2.6 at 5 min and did not change significantly at 60 min. Imaging of the monkey heart after injection of (18)F-FCPHA showed an initial spike of activity corresponding to blood flow followed by a plateau at 10 min. CONCLUSION: The cyclopropyl moiety in (18)F-FCPHA does have a significant influence on heart accumulation, as suggested by the high heart-to-blood ratio and the fast blood clearance in rats. These results, along with the remarkable quality of the PET images, indicate the potential of this new class of labeled fatty acids for use in studying heart disease by PET.
Animals↗
Testosterone administration attenuates regional brain hypometabolism in women with anorexia nervosa.
Abnormalities in brain metabolism have not been consistently well localized in anorexia nervosa (AN), and effects of specific therapies on these functional abnormalities have not been studied. Androgen replacement therapy improves mood, well-being and cognitive function in men with androgen deficiency. We therefore hypothesized that women with AN and relative androgen deficiency would exhibit regional brain hypometabolism compared with healthy controls, and that low-dose physiologic androgen replacement would attenuate the hypometabolism in some of these brain loci. We used FDG PET and statistical parametric mapping methods to investigate regional brain glucose metabolism in (1) 14 women with AN and 20 healthy control subjects of similar mean age and (2) women with AN after randomization to low-dose replacement testosterone therapy or placebo. Cerebral metabolism was decreased in the posterior cingulate, pregenual anterior cingulate, left middle temporal, right superior temporal, and left dorsolateral prefrontal cortex in the AN group compared with controls. In AN patients receiving testosterone, cerebral metabolism increased in the posterior cingulate, subgenual anterior cingulate, premotor cortex, right caudate and right parietal lobes. In conclusion, our data demonstrate distinct loci of regional brain hypometabolism in women with AN compared with controls. Moreover, abnormalities in one of these regions-the posterior cingulate cortex-were attenuated towards normal with low-dose testosterone replacement therapy. Further study is warranted to replicate these findings, as well as to determine their physiological and clinical significance.
Adult↗
Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.
The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.
Adenocarcinoma↗