QUANTIFICATION OF PULMONARY PATHOLOGY IN CYSTIC FIBROSIS-COMPARISON BETWEEN DIGITAL CHEST TOMOSYNTHESIS AND COMPUTED TOMOGRAPHY.

PURPOSE: Digital tomosynthesis (DTS) is currently undergoing validation for potential clinical implications. The aim of this study was to investigate the potential for DTS as a low-dose alternative to computed tomography (CT) in imaging of pulmonary pathology in patients with cystic fibrosis (CF). METHODS: DTS and CT were performed as part of the routine triannual follow-up in 31 CF patients. Extent of disease was quantified according to modality-specific scoring systems. Statistical analysis included Spearman's rank correlation coefficient (r) and Krippendorff's alpha (α). MAJOR FINDINGS: The median effective dose was 0.14 for DTS and 2.68 for CT. Intermodality correlation was very strong for total score and the subscores regarding bronchiectasis and bronchial wall-thickening (r = 0.82-0.91, P < 0.01). Interobserver reliability was high for total score, bronchiectasis and mucus plugging (α = 0.83-0.93) in DTS. CONCLUSION: Chest tomosynthesis could be a low-dose alternative to CT in quantitative estimation of structural lung disease in CF.

Capacity for 5-HT1A-mediated autoregulation predicts amygdala reactivity.

We examined the contribution of 5-HT1A autoreceptors (with [11C]WAY100635 positron emission tomography) to amygdala reactivity (with blood oxygenation level-dependent functional magnetic resonance imaging) in 20 healthy adult volunteers. We found a significant inverse relationship wherein 5-HT1A autoreceptor density predicted a notable 30-44% of the variability in amygdala reactivity. Our data suggest a potential molecular mechanism by which a reduced capacity for negative feedback regulation of 5-HT release is associated with increased amygdala reactivity.

Cerebral blood flow in hypertensive patients: an initial report of reduced and compensatory blood flow responses during performance of two cognitive tasks.

We asked whether the altered cerebral vasculature associated with essential hypertension might dampen or redirect the regional cerebral blood flow (rCBF) response to cognitive work. Relative rCBF was assessed with [(15)O]water positron emission tomography during a working memory task, a memory span task, and two perceptual control tasks. Unmedicated hypertensive patients and control subjects differed in rCBF response during both memory tasks. Hypertensives showed relatively diminished rCBF responses in right hemisphere areas combined with compensatory activation of homologous areas in the left cerebral cortex. Essential hypertension appears to selectively influence the circulatory reserve of portions of cerebral cortex and secondarily induce recruitment of other cortical areas to process certain tasks.

A fenfluramine-activated FDG-PET study of borderline personality disorder.

BACKGROUND: Impulsive aggression in patients with personality disorders is associated with diminished levels of cerebrospinal fluid (CSF) 5-HIAA, blunted neuroendocrine responses to serotonergic agonists, and decreased glucose utilization in the prefrontal cortex. We tested the hypothesis that impulsive aggression in borderline personality disorder (BPD) may be associated with diminished serotonergic regulation in the prefrontal cortex, using positron-emission tomography (PET) neuroimaging during pharmacologic challenge with d,l fenfluramine (FEN). METHODS: A 2-day, single-blind, placebo-controlled FEN challenge study was conducted in five patients with BPD (and no Axis I MDD) and eight healthy control participants. On Day 1, 4 mCi [(18)F]-fluorodeoxyglucose (FDG) was injected 3 hours after ingestion of placebo; on Day 2, FDG was injected 3 hours after ingestion of.8 mg/kg to 60 mg of d,l fenfluramine. After 30 min, a 45-min emission scan was acquired on the Siemans/CTI 951r/31 scanner. PET data were aligned to MR images and analyzed by Statistical Parametric Mapping (SPM96). RESULTS: In response to placebo, uptake of FDG was greater in control participants than patients in large areas of the prefrontal cortex including medial and orbital regions bilaterally (BA 10-11), left superior temporal gyrus, and right insular cortex. There were no areas in which patients had greater relative regional uptake than control participants. In response to FEN, relative regional uptake of FDG (relative to placebo) was greater in control participants compared to patients in medial and orbital regions of right prefrontal cortex (BA 10), left middle and superior temporal gyri (BA 22-23), left parietal lobe (BA 40), and left caudate body. CONCLUSIONS: Patients with BPD have diminished response to serotonergic stimulation in areas of prefrontal cortex associated with regulation of impulsive behavior.

Quantification of neuroreceptors in the living human brain: III. D2-like dopamine receptors: theory, validation, and changes during normal aging.

Dopamine receptor density is believed to decline in normal aging. To test this hypothesis, we measured the density of dopamine D2-like receptors in vivo in the neostriatum of normal living humans by using the graphical method. This method determines the D2-like dopamine receptor density in the human brain with an occupying ligand (unlabeled haloperidol) and a radioligand (labeled 3-N-methylspiperone). The method was examined critically, and the assumptions underlying the method were shown to be valid. The validation included comparison of the representation of tracer metabolism by high-pressure liquid chromatography and model assays, calculation of the lumped constant Dw from the value of its components, and comparable tracer partition coefficients in vitro and in vivo. In error analysis, the method consistently performed as well as the direct least-squares regression at statistical noise levels appropriate for the tomograph used in these studies. The method revealed that the density of the D2-like receptors that bind haloperidol in the caudate nucleus of normal humans declined 1% per year after the age of 18 years.

MR-based correction of brain PET measurements for heterogeneous gray matter radioactivity distribution.

Partial volume and mixed tissue sampling errors can cause significant inaccuracy in quantitative positron emission tomographic (PET) measurements. We previously described a method of correcting PET data for the effects of partial volume averaging on gray matter (GM) quantitation; however, this method may incompletely correct GM structures when local tissue concentrations are highly heterogeneous. We have extended this three-compartment algorithm to include a fourth compartment: a GM volume of interest (VOI) that can be delineated on magnetic resonance (MR) imaging. Computer simulations of PET images created from human MR data demonstrated errors of up to 120% in assigned activity values in small brain structures in uncorrected data. Four-compartment correction achieved full recovery of a wide range of coded activity in GM VOIs such as the amygdala, caudate, and thalamus. Further validation was performed in an agarose brain phantom in actual PET acquisitions. Implementation of this partial volume correction approach in [18F]fluorodeoxyglucose and [11C]-carfentanil PET data acquired in a healthy elderly human subject was also performed. This newly developed MR-based partial volume correction algorithm permits the accurate determination of the true radioactivity concentration in specific structures that can be defined by MR by accounting for the influence of heterogeneity of GM radioactivity.

Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness.

In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C]methyl-spiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.

Altered serotonin 2A receptor activity in women who have recovered from bulimia nervosa.

OBJECTIVE: The authors' goal was to confirm that brain serotonin (5-HT) alterations are present in patients who have recovered from bulimia nervosa. Positron emission tomography imaging with [(18)F]altanserin was used to characterize binding of the 5-HT(2A) receptor, which might contribute to altered feeding, mood, or impulse control. METHOD: Nine women who had recovered from bulimia nervosa (they had no episodes of binge eating or purging, were at normal weight, and had regular menstrual cycles for more than 1 year) were compared with 12 female volunteers who had never had bulimia. RESULTS: The healthy volunteers, but not the women who had recovered from bulimia nervosa, had an age-related decline in 5-HT(2A) binding. Women who had recovered from bulimia nervosa had a reduction of medial orbital frontal cortex 5-HT(2A) binding. CONCLUSIONS: The lack of age-related changes in 5-HT activity is further evidence of 5-HT alterations in subjects who have recovered from bulimia nervosa. In addition, vulnerabilities for eating disorders, impulse dyscontrol, and mood disturbances may involve 5-HT and frontal lobe activity.

Cerebral glucose metabolic response to combined total sleep deprivation and antidepressant treatment in geriatric depression.

OBJECTIVE: The treatment of geriatric depression is complicated by a variable and delayed response to antidepressant treatment. The present study was undertaken to test the hypothesis that combined total sleep deprivation and paroxetine treatment would produce a persistent reduction in glucose metabolism in the anterior cingulate cortex similar to that reported after long-term antidepressant treatment. METHOD: Six elderly depressed patients who met the DSM-IV criteria for major depressive disorder and six age-matched comparison subjects underwent serial positron emission tomography (PET) studies at baseline, after total sleep deprivation, after recovery sleep (after the initial paroxetine dose), and after 2 weeks of paroxetine treatment (patients only). The PET data were analyzed by using statistical parametric mapping methods. RESULTS: The patients' scores on a 13-item version of the Hamilton Depression Rating Scale were decreased after total sleep deprivation, after recovery sleep, and after 2 weeks of treatment. The Hamilton depression scores of the comparison subjects were not significantly altered. In the patients, the greatest reductions in normalized, relative glucose metabolism after sleep deprivation were observed in the anterior cingulate cortex (Brodmann area 24), and they persisted after recovery sleep and antidepressant treatment. The comparison subjects demonstrated increased metabolism in these areas. CONCLUSIONS: Improvement in the patients' depressive symptoms was accompanied by reduced glucose metabolism in the right anterior cingulate cortex and right medial frontal cortex. These preliminary data indicate that in elderly depressed patients, total sleep deprivation may accelerate the clinical and glucose metabolic response to antidepressant treatment.

Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression.

OBJECTIVE: This study examined whether evidence of cerebrovascular disease in the form of magnetic resonance imaging (MRI) signal hyperintensities in white matter was associated with depressive symptoms in a high-functioning group of normal elderly volunteers. METHOD: Ninety-two community-dwelling elderly individuals participating in a study of white matter hyperintensities (WMHs) in normal aging whose apolipoprotein E (APOE) genotype had been determined completed the Geriatric Depression Scale and received an MRI scan. Univariate analyses of variance were used to examine the relationship between depressive symptoms and the location of WMHs (in deep white matter versus in periventricular white matter) and to determine whether WMHs were more likely to be associated with symptoms of impaired motivation and concentration or with mood symptoms. The effect on depressive symptoms of the interaction between severity of cerebrovascular disease as evidenced by WMHs and APOE genotype was also examined. RESULTS: Hyperintensities in the deep white matter, but not in the periventricular white matter, were associated with depressive symptoms, especially symptoms of impaired motivation, concentration, and decision making. The relationship between deep WMHs and depressive symptoms was especially strong in individuals carrying the APOE-4 allele. CONCLUSIONS: The pattern of depressive symptoms associated with WMHs in this study was similar to the pattern described in the literature as characterizing "vascular" depression in older persons with major depression. The results suggest that cerebrovascular disease may also underlie the depressive symptoms often found in older individuals who are not clinically depressed.

PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders.

OBJECTIVE: To determine whether there are abnormalities in the in vivo status of the serotonin type 2A (5-HT2A) receptor in late-life depression and Alzheimer's disease, the authors used positron emission tomography (PET) to assess patients with these two conditions and healthy subjects. METHOD: PET was performed by using [18F]altanserin to evaluate 5-HT2A receptor binding in 11 elderly patients with depression (four men, seven women; mean age = 65.0 years, SD = 5.5); nine Alzheimer's disease patients, including three with concurrent depression (two men, seven women; mean age = 69.7 years, SD = 5.0); and 10 age-matched healthy subjects (four men, six women; mean age = 69.8 years, SD = 5.0). Partial-volume correction of regional specific binding estimates was performed by using a method based on magnetic resonance imaging. RESULTS: No significant abnormalities in [18F]altanserin binding (binding potential) were observed in the patients with late-life depression, and no effect of depression on binding potential was present within the Alzheimer's disease group. However, the patients with Alzheimer's disease had significantly lower binding than the normal subjects in several brain regions, including the anterior cingulate, prefrontal cortex, and sensorimotor cortex. CONCLUSIONS: These results suggest that the 5-HT2A receptor is differentially affected in late-life depression and Alzheimer's disease, a finding that has implications for the etiological basis of mood and cognitive features of neuropsychiatric disorders of late life.

Regional hypometabolism in Alzheimer's disease as measured by positron emission tomography after correction for effects of partial volume averaging.

Measurements of cerebral metabolism in patients with Alzheimer's disease (AD) using PET are artifactually depressed due to partial volume averaging of brain tissue activity with enlarged CSF spaces. To investigate the effects of correction for the expansion of CSF spaces on regional metabolic measures, as well as the correlations between neuropsychological test results and resting cerebral metabolism before and after partial volume correction, we applied an MRI-based method of partial volume correction to 18F-fluorodeoxyglucose (FDG)-PET data from eight patients diagnosed with probable AD and ten healthy elderly individuals. Before correction, the AD group had significantly lower cortex-to-cerebellum ratios in the posterior temporal, parietal, and frontal lobes in comparison to the control subjects. Partial volume correction of PET data resulted in 19 to 49% increases in regional activity in the AD group and 16 to 38% increases in the control group. The patients' persistence of significant hypometabolism in the frontal, posterior temporal, and parietal regions after partial volume correction suggests that a true reduction in regional cerebral glucose metabolism occurs in AD, even though its magnitude is a result of both metabolic reductions and the effects of atrophy. Partial volume correction of PET data in the AD group had a significant impact on the correlations between regional glucose metabolism and neuropsychological performance. These findings suggest that accounting for differential extent and distribution of cerebral atrophy in patients with AD and in healthy individuals may potentially improve our ability to interpret specific cognitive dysfunction in the context of the functional imaging data.

Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades: I.

OBJECTIVE: To describe the experience of a research clinic diagnosing AD during the last two decades, with special emphasis on patients who meet the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD, their patterns of clinical presentation, and neuropathologic outcomes. BACKGROUND: Probable AD has a heterogeneous clinical presentation, and can occur in the context of complicating factors. There are few reports, and none with this large of a sample, about the pattern of presentation, the nature of comorbidities, and the sensitivity and specificity of diagnosis. RESULTS: The AD Research Center of Pittsburgh examined 1139 patients with probable AD between April 1983 and February 2000. Of these 1139 probable AD patients, 29 (2.5%) had slow progression, 27 (2%) had rapid progression, 70 (6%) had an atypical presentation, and 85 (7%) had coexistent cerebrovascular disease. Confluent periventricular white matter lesions were found in 348 (30.5%) patients with probable AD. The overall sensitivity for the diagnosis of AD was 97% and the specificity 80%. However, the accuracy for the diagnosis of AD varied over the years: from 1983 to 1989, the sensitivity was 94% and specificity 52%, and from 1990 to 2000, the sensitivity was 98% and specificity 88%. CONCLUSION: Although the diagnosis of probable AD has been used to indicate the presence of a homogeneous clinical entity, these patients can vary in presentation, onset, or clinical course. This finding is of particular importance for the understanding of the pathophysiologic basis of the disease, and for the better identification of responders to dementia treatments. Although the sensitivity for the diagnosis of AD remained above 90% over the last two decades, the specificity increased, reflecting progressive improvement in the diagnosis of other dementing disorders.

Research evaluation and diagnosis of possible Alzheimer's disease over the last two decades: II.

OBJECTIVE: To describe the experience of a research clinic diagnosing possible AD during the last two decades. BACKGROUND: The National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for possible AD are generally used to indicate that a patient has AD in association with another disease process that could by itself cause dementia. There are no studies describing how these criteria should be applied, and there are no descriptions of functional and cognitive progression or survival in possible AD. METHODS: The authors examined the clinical characteristics of 267 patients diagnosed with possible AD at the AD Research Center of Pittsburgh from 1983 to 2000 and the likelihood of arriving at four endpoints: Mini-Mental State Examination score of /= 12, nursing home admission, and death. RESULTS: The possible AD classification has been simplified in six categories: possible AD with cerebrovascular disease (CVD) (69%), with history of alcohol abuse (15%), with history of depression (7%), with thyroid disease (4%), with history of head trauma (6%), with vitamin B12 deficiency (6%), and with other disease process that may have affected the clinical presentation of AD (4%). The presence of CVD, history of alcohol abuse, and history of depression concomitant with the onset of dementia were associated with time to death. Neither thyroid disease, history of head trauma, nor vitamin B12 deficiency were associated with any of the four endpoints. CONCLUSION: This cohort showed that comorbid conditions that can affect cognition delineate clearly defined subgroups in AD. The presence of environmental or other brain disorders sufficient to produce dementia appears to affect physical survival in patients with AD, but not functional and cognitive decline or institutionalization.

Transplantation of cultured human neuronal cells for patients with stroke.

Transplantation of cultured neuronal cells is safe in animal models and improves motor and cognitive deficits in rats with stroke. The authors studied the safety and feasibility of human neuronal cellular transplantation in patients with basal ganglia stroke and fixed motor deficits, including 12 patients (aged 44 to 75 years) with an infarct 6 months to 6 years previously (stable for at least 2 months). Serial evaluations (12 to 18 months) showed no adverse cell-related serologic or imaging-defined effects. The total European Stroke Scale score improved in six patients (3 to 10 points), with a mean improvement 2.9 points in all patients (p = 0. 046). Six of 11 PET scans at 6 months showed improved fluorodeoxyglucose uptake at the implant site. Neuronal transplantation is feasible in patients with motor infarction.

Serotonin in aging, late-life depression, and Alzheimer's disease: the emerging role of functional imaging.

Serotonin (5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life may contribute to behavioral changes commonly observed in the elderly population. Extensive evidence implicates a deficit in serotonergic neurotransmission in the development of major depression. It has been further suggested that the age-related changes in 5-HT neurons may predispose the elderly to develop depression. There is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimer's disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brain imaging with positron emission tomography (PET) in the in vivo study of the brain in aging depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioral features of aging and to define and monitor therapeutic regimens for neuropsychiatric conditions of late life. Coupling of clinical trials in well-characterized subject populations with PET imaging using ligands specific for 5-HT receptor subtypes and transporter proteins promises to increase our understanding of the role of the 5-HT system in affective and cognitive aspects of treatment response. Longitudinal studies in aging, late-life depression, and AD are also needed to evaluate the complex interplay between neurodegenerative processes and serotonergic neurotransmission.

Bilirubin, intraventricular hemorrhage, and phenobarbital in very low birth weight babies.

The relationships among serum bilirubin concentration on days 5 and 7, birth weight, the presence of intraventricular hemorrhage, and the receipt of phenobarbital were examined in a group of 232 newborns weighing less than 1,751 g who were intubated, mechanically ventilated by 12 hours after birth, and whose parents had given permission for a randomized trial of phenobarbital prophylaxis of intraventricular hemorrhage. The ratio of serum bilirubin concentration to birth weight (the bilirubin divided by birth weight index [BBI]) was used to examine the impact of 25 variables on a clinical guideline for therapy of hyperbilirubinemia in newborn infants. A linear regression model was used; the most powerful covariate was a birth weight less than 1.0 kg. The only other variable that reduced the BBI was phenobarbital receipt. The presence of intraventricular hemorrhage and ecchymoses had a significant influence increasing the BBI.

FDG imaging of spinal cord primitive neuroectodermal tumor.

PET with 18F-fluoro-2-deoxy-glucose (FDG) is well established as an effective imaging modality for evaluating suspected brain tumor recurrence. Use of FDG PET imaging for spinal cord neoplasms has not yet been studied, in large part due to limitations of spatial resolution. One report of FDG PET imaging of brain involvement with primitive neuroectodermal tumor (PNET) demonstrated mild hypometabolism relative to cortical gray matter. We demonstrate with FDG PET imaging the appearance of recurrent intramedullary PNET affecting the cervical spinal cord.

Fluorine-18-fluorodeoxyglucose uptake in pneumonia.

Whole-body PET imaging with 18F-fluorodeoxyglucose (FDG) has been shown to be effective in distinguishing benign and malignant pulmonary disease. Mild elevations in FDG uptake with standardized uptake values (SUVs) less than 2.5 have been reported in benign lesions, including pneumonia. We report a case of presumed bacterial pneumonia with markedly elevated FDG uptake in a patient with a concomitant squamous cell carcinoma in the contralateral lung. SUV's were similar for both lesions (4.9 and 5.4). This case demonstrates an inflammatory etiology for false-positive FDG PET imaging in the evaluation of focal pulmonary abnormalities.

Comparative evaluation of MR-based partial-volume correction schemes for PET.

UNLABELLED: Because of limitations of spatial resolution, quantitative PET measurements of cerebral blood flow, glucose metabolism and neuroreceptor binding are influenced by partial-volume averaging among neighboring tissues with differing tracer concentrations. METHODS: Two MR-based approaches to partial-volume correction of PET images were compared using simulations and a multicompartment phantom. The two-compartment method corrects PET data for the diluting effects of cerebrospinal fluid (CSF) spaces. The more complex three-compartment method also accounts for the effect of partial-volume averaging between gray and white matter. The effects of the most significant sources of error on MR-based partial-volume correction, including misregistration, resolution mismatch, segmentation errors and white matter heterogeneity, were evaluated. We also examined the relative usefulness of both approaches in PET studies of aging and neurodegenerative disease. RESULTS: Although the three-compartment method was highly accurate (with 100% gray matter recovery achieved in simulations), it was also more sensitive to all errors tested, particularly image segmentation and PET-MR registration. CONCLUSION: Based on these data, we conclude that the two-compartment approach is better suited for comparative PET studies, whereas the three-compartment algorithm is capable of greater accuracy for absolute quantitative measures.