Positron emission tomography/computed tomography as a clinical diagnostic tool for anterior mediastinal tumors.

PURPOSE: The purpose of this study was to assess the usefulness of positron emission tomography/computed tomography (PET/CT) in the differential diagnosis of anterior mediastinal tumors. METHODS: A total of 94 patients with anterior mediastinal masses or nodules (male, n = 41; female, n = 53; age, 17-84 years) were retrospectively evaluated. All patients were evaluated by PET/CT and the masses or nodules were histologically diagnosed in our institution. RESULTS: Anterior mediastinal masses and nodules were classified into two disease categories: Low (thymic hyperplasia, thymoma, mature teratoma, and MALT lymphoma) and High (thymic carcinoid, thymic cancer, diffuse large B-cell lymphoma, T-cell lymphoblastic lymphoma, Hodgkin's lymphoma, and malignant germ cell tumors) groups. The sensitivity and specificity of maximum standardized uptake value (SUVmax) 7.5 for the detection of High group were 77% and 100%, respectively. The SUVmax distributions of the WHO histological thymoma types and Masaoka stage thymomas extensively overlapped. Masaoka stage III thymomas had significantly higher SUVmax than Masaoka stage I thymomas. Regarding the TNM classification, the SUVmax of T3 and T1b thymomas was higher than T1a thymoma. CONCLUSION: Although the SUVmax of each disease overlapped, PET/CT findings provided useful information for the differential diagnosis of anterior mediastinal masses.

FDG-PET/CT of sarcoidosis and sarcoid reactions following antineoplastic treatment.

Sarcoidosis or sarcoid reactions, which appear as FDG-avid lesions in oncologic patients, need to be differentiated from disseminated malignancies. We aimed to promote awareness of development of sarcoidosis or sarcoid reactions after antineoplastic therapy to avoid diagnostic errors with FDG-PET/CT findings and assess the utility of FDG-PET/CT for follow-up. We retrospectively reviewed radiological reports of FDG-PET/CT scans performed between January 2009 and December 2011. Among oncologic patients with more than 2 FDG-PET/CT scans, those with nearly symmetrical increases in FDG uptake in the hilar or mediastinal lymph nodes were identified, and those with known sarcoidosis, concurrent diagnoses of sarcoidosis with malignancy, or histopathologically proven malignancies were excluded. Then, only those cases were selected for which sarcoidosis or sarcoid reactions were diagnosed. Four of 376 oncologic cases met the criteria. At 9 months to 6 years after antineoplastic therapy, abnormal FDG uptakes were observed in the hilar, mediastinal, abdominal, pelvic, and inguinal nodes, and/or spleen and lung parenchyma with SUVmax up to 17.7. On the basis of these findings, 1 patient received anticancer chemotherapy because of tumor recurrence suspicion. A gradual decrease in FDG uptake was observed on subsequent PET/CT scans. Sarcoidosis or sarcoid reactions should be considered in differential diagnosis of oncologic patients who have developed FDG-avid lesions any time after antineoplastic therapy. FDG-PET/CT can be used for follow-up in nondiagnostic situations to detect decreases in FDG uptake due to presence of sarcoidal granulomas.

Correlation between pulmonary function and brain volume in healthy elderly subjects.

INTRODUCTION: Cigarette smoking decreases brain regional gray matter volume and is related to chronic obstructive lung disease (COPD). COPD leads to decreased pulmonary function, which is represented by forced expiratory volume in one second percentage (FEV1.0 %); however, it is unclear if decreased pulmonary function is directly related to brain gray matter volume decline. Because there is a link between COPD and cognitive decline, revealing a direct relationship between pulmonary function and brain structure is important to better understand how pulmonary function affects brain structure and cognitive function. Therefore, the purpose of this study was to analyze whether there were significant correlations between FEV1.0 % and brain regional gray and white matter volumes using brain magnetic resonance (MR) image data from 109 community-dwelling healthy elderly individuals. METHODS: Brain MR images were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra procedure. RESULTS: We found a significant positive correlation between the regional white matter volume of the cerebellum and FEV1.0 % after adjusting for age, sex, and intracranial volume. CONCLUSION: Our results suggest that elderly individuals who have a lower FEV1.0 % have decreased regional white matter volume in the cerebellum. Therefore, preventing decreased pulmonary function is important for cerebellar white matter volume in the healthy elderly population.

A longitudinal study of age- and gender-related annual rate of volume changes in regional gray matter in healthy adults.

The aim of this study was to analyze correlations among the annual rate of gray matter volume change, age, gender, and cerebrovascular risk factors in 381 healthy community-dwelling subjects with a large age range by applying a longitudinal design over 6 years using brain magnetic resonance images (MRIs). Brain MRI data were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra procedure. The annual rate of regional gray matter volume change showed significant positive correlations with age in several regions, including the bilateral temporal pole, caudate nucleus, ventral and dorsolateral prefrontal cortices, insula, hippocampus, and temporoparietal cortex, whereas significant negative correlations with age were observed in several regions including the bilateral cingulate gyri and anterior lobe of the cerebellum. Additionally, a significant age-by-gender interaction was found for the annual rate of regional gray matter volume change in the bilateral hippocampus. No significant correlations were observed between the annual rate of regional gray matter volume change and body mass index or systolic blood pressure. A significant positive correlation between the annual rate of gray matter volume change and age indicates that the region shows not linear but accelerated gray matter loss with age. Therefore, evaluating the annual rate of the gray matter volume change with age in healthy subjects is important in understanding how gray matter volume changes with aging in each brain region and in anticipating what cognitive functions are likely to show accelerated decline with aging.

Correlation between high-sensitivity C-reactive protein and brain gray matter volume in healthy elderly subjects.

Although elevated serum high-sensitivity C-reactive protein (hsCRP) is related to atherosclerosis, brain infarction, and cognitive decline, it has not been clarified whether increased hsCRP is associated with the decline in brain gray matter volume. Therefore, the purpose of this study was to determine the relationship between hsCRP levels and brain regional gray matter volume using brain magnetic resonance imaging (MRI) data from 109 community-dwelling healthy elderly subjects. Brain MRIs were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra (DARTEL) procedure. We found a significant negative correlation between regional gray matter volume of the posterior and lateral aspects of the left temporal cortex and hsCRP level after adjusting for age, gender, and intracranial volume. Our results suggest that subjects who have mild inflammation related to arteriosclerosis have decreased regional gray matter volume in the posterior and lateral aspects of the left temporal cortex. Thus, preventing the progression of arteriosclerosis may be important for preventing a decrease in gray matter volume in healthy elderly subjects.

A longitudinal study of the relationship between personality traits and the annual rate of volume changes in regional gray matter in healthy adults.

To investigate whether personality traits affect the rate of decline of gray matter volume, we analyzed the relationships between personality traits and the annual rate of changes of gray matter volume in 274 healthy community dwelling subjects with a large age range by applying a longitudinal design over 6 years, using brain magnetic resonance images (MRI) and the Revised NEO Personality Inventory (NEO-PI-R) at baseline. Brain MRI data were processed using voxel-based morphometry with a custom template by applying the DARTEL diffeomorphic registration tool. For each subject, we used NEO-PI-R to evaluate the five major personality traits, including neuroticism, extraversion, openness, agreeableness, and conscientiousness. The results show that the annual rate of change in regional gray matter volume in the right inferior parietal lobule was correlated significantly and negatively with a personality of openness, which is known to be related to intellect, intellectual curiosity, and creativity adjusting for age, gender, and intracranial volume. This result indicates that subjects with a personality trait of less openness have an accelerated loss of gray matter volume in the right inferior parietal lobule, compared with subjects with a personality trait of more openness. Because the right inferior parietal lobule is involved in higher cognitive function such as working memory and creativity, a personality trait of openness is thought to be important for preserving gray matter volume and cognitive function of the right inferior parietal lobule in healthy adults.

Age-related changes in topological organization of structural brain networks in healthy individuals.

The aim of this study was to examine structural brain networks using regional gray matter volume, as well as to investigate changes in small-world and modular organization with normal aging. We constructed structural brain networks composed of 90 regions in young, middle, and old age groups. We randomly selected 350 healthy subjects for each group from a Japanese magnetic resonance image database. Structural brain networks in three age groups showed economical small-world properties, providing high global and local efficiency for parallel information processing at low connection cost. The small-world efficiency and node betweenness varied significantly and revealed a U- or inverted U-curve model tendency among three age groups. Results also demonstrated that structural brain networks exhibited a modular organization in which the connections between regions are much denser within modules than between them. The modular organization of structural brain networks was similar between the young and middle age groups, but quite different from the old group. In particular, the old group showed a notable decrease in the connector ratio and the intermodule connections. Combining the results of small-world efficiency, node betweenness and modular organization, we concluded that the brain network changed slightly, developing into a more distributed organization from young to middle age. The organization eventually altered greatly, shifting to a more localized organization in old age. Our findings provided quantitative insights into topological principles of structural brain networks and changes related to normal aging.

Correlations among brain gray matter volumes, age, gender, and hemisphere in healthy individuals.

To determine the relationship between age and gray matter structure and how interactions between gender and hemisphere impact this relationship, we examined correlations between global or regional gray matter volume and age, including interactions of gender and hemisphere, using a general linear model with voxel-based and region-of-interest analyses. Brain magnetic resonance images were collected from 1460 healthy individuals aged 20-69 years; the images were linearly normalized and segmented and restored to native space for analysis of global gray matter volume. Linearly normalized images were then non-linearly normalized and smoothed for analysis of regional gray matter volume. Analysis of global gray matter volume revealed a significant negative correlation between gray matter ratio (gray matter volume divided by intracranial volume) and age in both genders, and a significant interaction effect of age × gender on the gray matter ratio. In analyzing regional gray matter volume, the gray matter volume of all regions showed significant main effects of age, and most regions, with the exception of several including the inferior parietal lobule, showed a significant age × gender interaction. Additionally, the inferior temporal gyrus showed a significant age × gender × hemisphere interaction. No regional volumes showed significant age × hemisphere interactions. Our study may contribute to clarifying the mechanism(s) of normal brain aging in each brain region.

The overlapping community structure of structural brain network in young healthy individuals.

Community structure is a universal and significant feature of many complex networks in biology, society, and economics. Community structure has also been revealed in human brain structural and functional networks in previous studies. However, communities overlap and share many edges and nodes. Uncovering the overlapping community structure of complex networks remains largely unknown in human brain networks. Here, using regional gray matter volume, we investigated the structural brain network among 90 brain regions (according to a predefined anatomical atlas) in 462 young, healthy individuals. Overlapped nodes between communities were defined by assuming that nodes (brain regions) can belong to more than one community. We demonstrated that 90 brain regions were organized into 5 overlapping communities associated with several well-known brain systems, such as the auditory/language, visuospatial, emotion, decision-making, social, control of action, memory/learning, and visual systems. The overlapped nodes were mostly involved in an inferior-posterior pattern and were primarily related to auditory and visual perception. The overlapped nodes were mainly attributed to brain regions with higher node degrees and nodal efficiency and played a pivotal role in the flow of information through the structural brain network. Our results revealed fuzzy boundaries between communities by identifying overlapped nodes and provided new insights into the understanding of the relationship between the structure and function of the human brain. This study provides the first report of the overlapping community structure of the structural network of the human brain.

Correlation between gray/white matter volume and cognition in healthy elderly people.

This study applied volumetric analysis and voxel-based morphometry (VBM) of brain magnetic resonance (MR) images to assess whether correlations exist between global and regional gray/white matter volume and the cognitive functions of semantic memory and short-term memory, which are relatively well preserved with aging, using MR image data from 109 community-dwelling healthy elderly individuals. We used the Information and Digit Span subtests of the Wechsler Adult Intelligent Scale-Revised as measures of semantic memory and short-term memory, respectively. We found significant positive correlations between the gray matter ratio, the percentage of gray matter volume in the intracranial volume, and performance on the Digit Span subtest, and between the regional gray matter volumes of the bilateral anterior temporal lobes and performance on the Information subtest. No significant correlations between performance on the cognitive tests and white matter volume were found. Our results suggest that individual variability in specific cognitive functions that are relatively well preserved with aging is accounted for by the variability of gray matter volume in healthy elderly subjects.

Correlation between baseline regional gray matter volume and global gray matter volume decline rate.

Evaluating whole-brain or global gray matter volume decline rate is important in distinguishing neurodegenerative diseases from normal aging and in anticipating cognitive decline over a given period in non-demented subjects. Whether a significant negative correlation exists between baseline regional gray matter volume of several regions and global gray matter volume decline in the subsequent time period in healthy subjects has not yet been clarified. Therefore, we analyzed the correlation between baseline regional gray matter volumes and the rate of global gray matter volume decline in the period following baseline using magnetic resonance images of the brains of 381 healthy subjects by applying a longitudinal design over 6 years using voxel-based morphometry. As a result, the annual percentage change in gray matter ratio (GMR, APC(GMR)), in which GMR represents the percentage of gray matter volume in the intracranial volume, showed a significant negative correlation with the baseline regional gray matter volumes of the right posterior cingulate cortex/precuneus and the left hippocampus. Additionally, baseline regional gray matter volume of both the right PCC/precuneus and the left hippocampus significantly distinguished whether the APC(GMR) was above or below the mean of APC(GMR). Our results suggest that baseline regional gray matter volume predicts the rate of global gray matter volume decline in the subsequent period in healthy subjects. Our study may contribute to distinguishing neurodegenerative diseases from normal aging and to predicting cognitive decline.

Correlation between degree of white matter hyperintensities and global gray matter volume decline rate.

INTRODUCTION: Whether the degree of white matter hyperintensities (WMHs) shows a significant correlation with the rate of global gray matter volume decline over a period following initial baseline measurement remains unclear. The purpose of the present study was to reveal the relationship between the degree of WMHs at baseline and the rate of global gray matter volume decline by applying a longitudinal design. METHODS: Using a 6-year longitudinal design and magnetic resonance images of the brains of 160 healthy individuals aged over 50 years and living in the community, we analyzed the correlation between degree of WMHs using Fazekas scaling at baseline and rate of global gray matter volume decline 6 years later. To obtain the rate of global gray matter volume decline, we calculated global gray matter volume and intracranial volume at baseline and at follow-up using a fully automated method. RESULTS: The annual percentage change in the gray matter ratio (GMR, APC(GMR)), in which GMR represents the percentage of gray matter volume in the intracranial volume, showed a significant positive correlation with the degree of deep WMHs and periventricular WMHs at baseline, after adjusting for age, gender, present history of hypertension, and diabetes mellitus. CONCLUSION: Our results suggest that degree of WMHs at baseline predicts the rate of gray matter volume decline 6 years later and that simple visual scaling of WMHs could contribute to predicting the rate of global gray matter volume decline.

A longitudinal study of gray matter volume decline with age and modifying factors.

The rate at which the volume of gray matter declines with normal aging, and whether gender or generational differences affect this rate, remain unclear. Using a longitudinal design over 6 years in 381 healthy community-dwelling individuals, we examined the rate of age-related loss in global gray matter volume, and how gender, generational and cerebrovascular risk factors affected this rate. We collected brain magnetic resonance images of the subjects, and calculated gray matter and intracranial volumes at baseline and follow-up using a fully automated technique. Using these volumes we then calculated the gray matter ratio (GMR), which measures gray matter volume as a percentage of the total intracranial volume. There were significant main effects of age, gender, and body mass index, and an age×gender interaction in the annual percentage change in the GMR (APC(GMR)). The APC(GMR) of younger women was lower than that in older women and men. Our results may help in understanding the mechanism(s) of normal brain aging, and in distinguishing neurodegenerative diseases from normal aging.

A bone marrow F-18 FDG uptake exceeding the liver uptake may indicate bone marrow hyperactivity.

OBJECTIVE: In clinical positron emission tomography (PET) studies for oncology, it is occasionally required to differentiate a diffuse increase in bone marrow (BM) F-18 fluoro-2-deoxyglucose (FDG) uptake due to the involvement of malignancy or hematopoietic disease and that due to the administration of hematopoietic cytokines, an inflammation reaction, or stimulation by some types of malignancy. The objectives of this study were to clarify the relationships between BM F-18 FDG uptake and blood parameters as well as age, and also to determine the degree of F-18 FDG accumulation that constitutes an abnormal level referring to blood parameters. METHODS: Records of 65 patients, 32 with benign diseases and 33 with malignancies without metastasis in bone and liver until a half year after the PET examination, were analyzed retrospectively. Regions of interest were placed on the liver and the lower thoracic and lumbar vertebrae to measure the standardized uptake value (SUV), and vertebral SUVs were averaged as the BM SUV(mean). The BM SUV(mean) was divided by the liver SUV to calculate the BM/liver ratio. The relationships among the BM SUV(mean), or BM/liver ratio, and blood parameters and age were tested using multiple regression analysis. RESULTS: In both patients with and without malignancy, a multiple regression model using the BM/liver ratio showed a higher coefficient of determination value than that using the BM SUV(mean), indicating that the correction by the liver SUV reduced the interindividual variation in the BM SUV(mean). The BM/liver ratio was negatively correlated with age (beta = -0.41 and -0.43, respectively) and positively correlated with serum C-reactive protein (CRP) level (beta = 0.39 and 0.46, respectively) in both groups of patients. Every patient with benign disease who had a ratio greater than or equal to 1 had an increased CRP level. CONCLUSIONS: The BM F-18 FDG uptake depends on the patient's age and serum CRP level, both with and without malignancy. A BM F-18 FDG uptake greater than or equal to that of the liver may indicate BM activation.

(18)FDG uptake associated with CT density on PET/CT in lungs with and without chronic interstitial lung diseases.

OBJECTIVE: The dependent-density of computed tomography (CT) images of positron emission tomography (PET)/CT is sometimes difficult to distinguish from chronic interstitial lung disease (ILD) when it accompanies increased (18)F-fluorodeoxy-D: -glucose ((18)FDG) uptake. Though the possible utility of (18)FDG-PET for the diagnosis of active ILD has been reported, the clinical relevance of mild lung (18)FDG uptake in ILD cases without signs and symptoms suggesting acute progression has not been described. This study aimed to test relationships between (18)FDG uptake and lung density on CT using PET/CT in patients with normal lung as well as clinically stable chronic ILD. METHODS: Thirty-six patients with normal lungs (controls) and 28 patients with chronic ILD (ILD cases) without acute exacerbation were retrospectively selected from (18)FDG-PET/CT scans performed in examination of malignant neoplasms. Elliptical regions of interest (ROIs) were placed on the lung. The relationships between CT density and (18)FDG uptake between the control and ILD cases were tested. RESULTS: The CT density and (18)FDG uptake had a linear correlation in both the controls and the ILD cases without a difference in their regression slopes, and they were overlapped between the controls and the ILD cases with higher mean values in the ILD cases. CONCLUSIONS: Lung (18)FDG uptake was considered to reflect a gravity-dependent tissue density in the normal lung. Though the lung (18)FDG uptake as well as the CT density tended to be higher in chronic ILD patients, it may be difficult to distinguish them in normal dependent regions from those related to chronic ILD in some cases.

Increase of serum CA19-9 level without an evident lesion on conventional imaging is insufficient for justification of 18FDG-PET examination.

BACKGROUND/AIMS: The serum tumor marker carbohydrate associated antigen 19-9 (CA19-9) has been used for screening for cancer, because its increase has been associated with many cancers. We aimed to evaluate the clinical value of positron emission tomography using F-18 fluorodeoxyglucose (18FDG-PET) that was prompted by increases of serum CA19-9 without findings on conventional imaging. METHODOLOGY: Twenty-two patients were retrospectively selected. Eleven were without a history of cancer and eleven had a history of cancer and were treated with curative intent. All 18FDG-PET findings were compared with the findings of histopathology by surgery or biopsy, or clinical follow-up for at least 1 year. RESULTS: We found only two true positive cases, and eleven cases without a cancer history included 10 true negatives and one false positive. CONCLUSIONS: Increases in serum CA19-9 are caused by many benign conditions. Increases of CA19-9 without findings on conventional imaging do not justify 18FDG-PET examination, particularly in patients without a cancer history.

Relationship between body mass index and gray matter volume in 1,428 healthy individuals.

OBJECTIVE: To investigate any correlation between BMI and brain gray matter volume, we analyzed 1,428 healthy Japanese subjects by applying volumetric analysis and voxel-based morphometry (VBM) using brain magnetic resonance (MR) imaging, which enables a global analysis of brain structure without a priori identification of a region of interest. METHODS AND PROCEDURES: We collected brain MR images from 690 men and 738 women, and their height, weight, and other clinical information. The collected images were automatically normalized into a common standard space for an objective assessment of neuroanatomical correlations in volumetric analysis and VBM with BMI. RESULTS: Volumetric analysis revealed a significant negative correlation in men (P < 0.001, adjusting for age, lifetime alcohol intake, history of hypertension, and diabetes mellitus), although not in women, between BMI and the gray matter ratio, which represents the percentage of gray matter volume in the intracranial volume. VBM revealed that, in men, the regional gray matter volume of the bilateral medial temporal lobes, anterior lobe of the cerebellum, occipital lobe, frontal lobe, precuneus, and midbrain showed significant negative correlations with BMI, while those of the bilateral inferior frontal gyri, posterior lobe of the cerebellum, frontal lobes, temporal lobes, thalami, and caudate heads showed significant positive correlations with BMI. DISCUSSION: Global loss and regional alterations in gray matter volume occur in obese male subjects, suggesting that male subjects with a high BMI are at greater risk for future declines in cognition or other brain functions.

Diagnosing active inflammation in the SAPHO syndrome using 18FDG-PET/CT in suspected metastatic vertebral bone tumors.

The vertebral spine is frequently affected by the SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome. We report the collective imaging findings of hybrid F-18 fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT), as well as bone scans and magnetic resonance imaging, in a patient who had suspected metastatic vertebral bone tumors. 18FDG-PET/CT can be utilized to exclude metastatic vertebral tumors, as well as identifying stable lesions, by demonstrating active inflammatory lesions with accurate anatomic localization through the convergence of the functional information from 18FDG uptake with the anatomic information of CT.

Diffuse bone marrow uptake on F-18 FDG PET in patients with myelodysplastic syndromes.

It is well known that hematopoietic cytokine stimulation can cause diffuse increase of FDG accumulation in bone marrow on PET imaging, which simulates that seen in patients with bone marrow metastases. However, diffuse bone marrow FDG uptake can be caused by other etiologies. We report 2 patients who did not have a history of hematopoietic cytokine stimulation. The FDG PET images showed diffuse bone marrow FDG uptake, and the patients were diagnosed as having myelodysplastic syndromes. These cases demonstrate that diffuse FDG uptake by bone marrow can suggest neoplastic disease of the hematopoietic tissues.

Both global gray matter volume and regional gray matter volume negatively correlate with lifetime alcohol intake in non-alcohol-dependent Japanese men: a volumetric analysis and a voxel-based morphometry.

BACKGROUND: Non-alcohol-dependent heavy drinkers, as well as alcohol-dependent individuals, show brain atrophy. The purpose of this study was to evaluate whether there are correlations between global and regional gray matter volumes and the lifetime alcohol intake using volumetric analysis and voxel-based morphometry (VBM) among Japanese non-alcohol-dependent male individuals. METHODS: High-resolution three-dimensional magnetic resonance images were acquired from 405 Japanese non-alcohol-dependent male individuals. The collected images were normalized, segmented for volumetric analysis, and additionally smoothed for VBM. For volumetric analysis, the partial correlation coefficient was estimated between the gray matter ratio, which represents the percentage of gray matter volume in the intracranial volume, and the lifetime alcohol intake adjusted for the age of each subject. Multiple regression analysis was performed among regional gray matter volume, lifetime alcohol intake, and age using VBM. RESULTS: Volumetric analysis revealed that gray matter ratio showed a negative correlation with the lifetime alcohol intake adjusted for age (p=0.059, partial correlation coefficient=-0.091). The VBM revealed that the gray matter volumes of the bilateral middle frontal gyri showed a significant negative correlation with the lifetime alcohol intake adjusted for age and systolic blood pressure (left side, p=0.006, Z=4.77; right side, p=0.023, Z=4.45, and p=0.046, Z=4.27). CONCLUSIONS: Our study suggests that non-alcohol-dependent Japanese male individuals show that both global gray matter volume and regional gray matter volume have negative correlations with the lifetime alcohol intake. Our study may contribute to clarifying the mechanism underlying the brain structural changes because of alcohol influence in healthy non-alcohol-dependent individuals.