Diffusion tensor measures of the corpus callosum in adolescents with adolescent onset alcohol use disorders

Background: In adults, myelination injury is associated with alcoholism. Maturation of the corpus callosum is prominent during adolescence. We hypothesized that subjects with adolescent‐onset alcohol use disorders (AUD; defined as Diagnostic and Statistical Manual of Mental Disorders‐IV alcohol dependence or abuse) would have myelination mircostructural differences compared to controls. Methods: Adolescent subjects (25 males, 7 females) with an AUD (16.9 ± 1.2 years), who were recruited from substance abuse treatment programs and had co‐morbid mental disorders, and 28 sociodemographically similar healthy controls (17 males, 11 females; 15.9 ± 1.1 years) underwent a 3.0 T MRI diffusion tensor imaging scan. Results: Measures of rostral body fractional anisotropy (FA) were higher in the AUD group than in the control group. Compared to controls, mean diffusivity (MD) was lower, while FA was higher, in the AUD group in the isthmus region. Anterior corpus callosum mircostructural development differed in adolescents with AUD, as age was positively (not negatively) associated with rostrum MD and age was negatively (not positively) associated with rostrum FA. There were sex by group interactions in that control females had higher posterior midbody FA when compared to female adolescents with AUD. Conclusions: Lower MD and higher FA values in the AUD group suggest pre‐morbid vulnerability for accelerated prefrontal and temporo‐parietal myelin maturation that may enhance the risk for adolescent AUD. Significant (and opposite to developmentally expected) correlations were seen between anterior corpus callosum MD and FA measures and age in the AUD group, suggesting neurotoxic effects of alcohol on adolescent corpus callosum microstructure. As seen in adults, female adolescents with AUD may be especially vulnerable to corpus callosum mircostructural injury. Further diffusion tensor imaging studies of corpus callosum maturation in children at familial risk for alcoholism, and in those with AUD, need to be done to elucidate these mechanisms.     

Extensive deep gray matter volume reductions in children and adolescents with fetal alcohol spectrum disorders

Background: The link between the numerous cognitive, motor, and behavioral difficulties of individuals with fetal alcohol spectrum disorders (FASD) and underlying specific structural brain injuries can be investigated using high‐resolution imaging. Differential sensitivity of the brain’s “relay” stations, namely the deep gray matter structures, may play a key factor given their multifaceted role in brain function. The purpose of our study was to analyze differences in deep gray matter volumes of children and adolescents with FASD relative to age/sex‐matched controls and to examine whether any volume differences were consistent across the age range of neurodevelopment. Methods: Children and adolescents (N = 28, 6 to 17 years) diagnosed with FASD and 56 age‐ and sex‐matched healthy controls (i.e., 2 matched controls per FASD subject) underwent 3‐dimensional T1‐weighted MRI scans that were used for the automated volume measurement (FreeSurfer) of the intracranial space, total white matter, cortical gray matter, and 6 deep gray matter structures, namely the hippocampus, amygdala, thalamus, caudate, putamen, and globus pallidus, with left and right measured separately. Volumes were compared between FASD and controls, as well as changes with age. Results: Significant reductions of volume in FASD were observed for the intracranial vault (7.6%), total white matter (8.6%), total cortical gray matter (7.8%), and total deep gray matter (13.1%). All 6 deep gray matter structures showed significant volume reductions bilaterally with the caudate (approximately 16%) and globus pallidus (approximately 18%) being most affected. The hippocampus, thalamus, and globus pallidus showed reductions in all 3 age subgroups (6 to 9, 10 to 13, and 14 to 17 years) but the caudate and putamen had smaller volumes for FASD only within the 2 youngest subgroups; the amygdala was only smaller for FASD in the 2 oldest subgroups. Conclusions: Significant, but variable, volume reductions throughout the deep gray matter are observed over a wide age range of 6 to 17 years in FASD.     

缺血性卒中患者的脑白质病变

脑白质病变(white matter lesion,WML)是一种常见的神经影像学改变.随着人口老龄化和成像技术的发展,WML在老年人中的检出率逐渐增高.WML与缺血性卒中关系密切.文章对WML的病理生理学机制、影像学评价、临床表现、与缺血性卒中的关系以及预防和治疗进行了综述.     

Brain metabolic alterations in adolescents and young adults with fetal alcohol spectrum disorders

BACKGROUND: Prenatal alcohol exposure affects brain structure and function. This study examined brain metabolism using magnetic resonance spectroscopy (MRS) and searched for regions of specific vulnerability in adolescents and young adults prenatally exposed to alcohol. METHODS: Ten adolescents and young adults with confirmed heavy prenatal alcohol exposure and a diagnosis within the fetal alcohol spectrum disorders (FASD) were included. Three of them had fetal alcohol syndrome (FAS), 3 had partial FAS (PFAS), and 4 had alcohol-related neurobehavioral disorder (ARND). The control group consisted of 10 adolescents matched for age, sex, head circumference, handedness, and body mass. Exclusionary criteria were learning disorders and prenatal alcohol exposure. Three-dimensional (1)H magnetic resonance spectroscopic imaging ((1)H MRSI) was performed in the cerebrum and cerebellum. Metabolite ratios N-acetylaspartate/choline (NAA/Cho), NAA/creatine (Cr) and Cho/Cr, and absolute metabolite intensities were calculated for several anatomic regions. RESULTS: In patients with FASD, lower NAA/Cho and/or NAA/Cr compared with controls were found in parietal and frontal cortices, frontal white matter, corpus callosum, thalamus, and cerebellar dentate nucleus. There was an increase in the absolute intensity of the glial markers Cho and Cr but no change in the neuronal marker NAA. CONCLUSIONS: Our results suggest that prenatal alcohol exposure alters brain metabolism in a long-standing or permanent manner in multiple brain areas. These changes are in accordance with previous findings from structural and functional studies. Metabolic alterations represent changes in the glial cell pool rather than in the neurons.     

Altered brain activation by a false recognition task in young abstinent patients with alcohol dependence

BACKGROUND: Heavy alcohol intake induces both structural and functional changes in the central nervous system. Recent research developments converged on the idea that even in patients with alcohol dependence without apparent structural brain changes, some cognitive impairment exists, and associated functional change could be visualized by neuroimaging techniques. However, these data were from old (more than 50 years) patients using working memory and response inhibition tasks. Whether young abstinent patients show aberrant signs of brain activation is a matter of interest, specifically by the long-term memory retrieval task. METHODS: Subjects were 9 young patients with alcohol dependence with long-term abstinent (8 males and 1 female) and age- and education-matched 9 healthy controls (7 males and 2 females). We used a modified false recognition task in a functional MRI study. RESULTS: The young patients with alcohol dependence showed reduced activation in the right dorsolateral prefrontal cortex, anterior cingulate cortex (ACC), left pulvinar in the thalamus, and in the right ventral striatum, although behavioral performances and regional patterns of brain activation were similar between patients and controls. CONCLUSIONS: Long-term memory retrieval induced altered activations in prefrontal lobes, ACC, thalamus, and ventral striatum in young patients with alcohol dependence. These findings were correspondent to deficits of goal directed behavior, monitoring the erroneous responses, memory function, and drug-seeking behavior. Furthermore, these reduced activations can be considered as latent "lesions," suggesting subclinical pathology in alcoholic brains.     

Diffusion tensor imaging in children with fetal alcohol spectrum disorders

BACKGROUND: Prenatal alcohol exposure, which is associated with macrostructural brain abnormalities, neurocognitive deficits, and behavioral disturbances, is characterized as fetal alcohol syndrome (FAS) in severe cases. The only published study thus far using diffusion tensor imaging (DTI) showed microstructural abnormalities in patients with FAS. The current study investigated whether similar abnormalities are present in less severely affected, prenatally exposed patients who did not display all of the typical FAS physical stigmata. METHODS: Subjects included 14 children, ages 10 to 13, with fetal alcohol spectrum disorders (FASD) and 13 matched controls. Cases with full-criteria FAS, mental retardation, or microcephaly were excluded. Subjects underwent MRI scans including DTI. RESULTS: Although cases with microcephaly were excluded, there was a trend toward smaller total cerebral volume in the FASD group (p=0.057, Cohen's d effect size =0.73). Subjects with FASD had greater mean diffusivity (MD) in the isthmus of the corpus callosum than controls (p=0.013, effect size =1.05), suggesting microstructural abnormalities in this region. There were no group differences in 5 other regions of the corpus callosum. Correlations between MD in the isthmus and facial dysmorphology were nonsignificant. CONCLUSIONS: These results suggest that even relatively mild forms of fetal alcohol exposure may be associated with microstructural abnormalities in the posterior corpus callosum that are detectable with DTI.     

Neurocognitive functioning of adolescents: effects of protracted alcohol use

BACKGROUND: The present study examined associations between alcohol involvement in early to middle adolescence and neuropsychological (NP) functioning. METHODS: Alcohol-dependent adolescents (n = 33) with over 100 lifetime alcohol episodes and without dependence on other substances were recruited from alcohol/drug abuse treatment facilities. Comparison (n = 24) adolescents had no histories of alcohol or drug problems and were matched to alcohol-dependent participants on age (15 to 16 years), gender, socioeconomic status, education, and family history of alcohol dependence. NP tests and psychosocial measures were administered to alcohol-dependent participants following 3 weeks of detoxification. RESULTS: Alcohol-dependent and comparison adolescents demonstrated significant differences on several NP scores. Protracted alcohol use was associated with poorer performance on verbal and nonverbal retention in the context of intact learning and recognition discriminability. Recent alcohol withdrawal among adolescents was associated with poor visuospatial functioning, whereas lifetime alcohol withdrawal was associated with poorer retrieval of verbal and nonverbal information. CONCLUSIONS: Deficits in retrieval of verbal and nonverbal information and in visuospatial functioning were evident in youths with histories of heavy drinking during early and middle adolescence.     

Neuroimaging in Alcoholism: Ethanol and Brain Damage

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) μ-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.     

Cigarette smoking and the risk for alcohol use disorders among adolescent drinkers

BACKGROUND: Cigarette smoking and alcohol use disorders (AUDs) are closely linked, but it is not clear whether higher rates of AUD among smokers are solely attributable to heavier drinking or, alternatively, whether smokers are more vulnerable to alcohol abuse and dependence than nonsmokers who drink comparable quantities. We sought to address this issue using data from a nationally representative U.S. sample of adolescents and young adults. Specifically, we analyzed the relationship between cigarette smoking, drinking, and AUDs. METHODS: Data were from the aggregated 2002 through 2004 U.S. National Survey on Drug Use and Health. Participants were randomly selected, household-dwelling adolescents and young adults (ages 12-20) from the noninstitutionalized, civilian population of the United States (N=74,836). Measurements included current DSM-IV alcohol abuse or dependence, number of drinks in the past 30 days, and past-year cigarette smoking, defined as having smoked more than 100 cigarettes across the lifetime and having smoked during the past year. RESULTS: Past-year smokers (prevalence=16.0%) drank in higher quantities than never-smokers, but were also at elevated risk for AUD when compared with never-smokers who drank equivalent quantities. The effect was observed across age groups, but was more prominent among younger adolescents. After adjusting for drinking quantity and sociodemographic variables, smokers had 4.5-fold higher odds of AUD than never-smokers [95% confidence interval (95% CI), 3.1-6.6]. Youths who reported smoking but did not cross the 100-cigarette threshold were at intermediate risk [odds ratio (OR), 2.3; 95% CI, 1.7-3.3]. Differences in AUD between smokers and never-smokers were most pronounced at lower levels of drinking. CONCLUSIONS: The results are consistent with a higher vulnerability to AUDs among smokers, compared with nonsmokers who drink equivalent quantities.     

Brain diffusion abnormalities in children with fetal alcohol spectrum disorder

Background: Children with fetal alcohol spectrum disorder (FASD) have a variety of cognitive, behavioral, and neurological impairments, including structural brain damage. Despite the importance of white matter connections for proper brain function, little is known about how these connections, and the deep gray matter structures that act as relay stations, are affected in children with FASD. The purpose of this study was to use diffusion tensor imaging, an advanced magnetic resonance imaging technique, to examine microstructural differences of white and deep gray matter in children with FASD. Methods: Subjects were 24 children aged 5–13 years previously diagnosed with FASD and 95 healthy children over the same age range. Diffusion tractography was used to delineate 10 major white matter tracts in each individual, and region‐of‐interest analysis was used to assess 4 deep gray matter structures. Fractional anisotropy, an indicator of white matter integrity, and mean diffusivity, a measure of the average water diffusion, were assessed in all 14 brain structures. Results: Diffusion tensor imaging revealed significant differences of diffusion parameters in several areas of the brain, including the genu and splenium of the corpus callosum, cingulum, corticospinal tracts, inferior fronto‐occipital fasciculus, inferior and superior longitudinal fasciculi, globus pallidus, putamen, and thalamus. Reduced white and gray matter volumes, as well as total brain volume, were observed in the FASD group. Conclusions: These results demonstrate diffusion abnormalities in FASD beyond the corpus callosum and suggest that several specific white matter regions, particularly commissural and temporal connections, and deep gray matter areas of the brain are sensitive to prenatal alcohol exposure.     

Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults with adolescent-onset alcohol use disorders and comorbid mental disorders

BACKGROUND: In adults, prefrontal, thalamic, and cerebellar brain injury is associated with excessive ethanol intake. As these brain structures are actively maturing during adolescence, we hypothesized that subjects with adolescent-onset alcohol use disorders, compared with control subjects, would have smaller brain volumes in these areas. Thus, we compared prefrontal-thalamic-cerebellar measures of adolescents and young adults with adolescent-onset alcohol use disorders (AUD, defined as DSM-IV alcohol dependence or abuse) with those of sociodemographically similar control subjects. METHODS: Magnetic resonance imaging was used to measure prefrontal cortex, thalamic, and cerebellar volumes in 14 subjects (eight males, six females) with an AUD (mean age, 17.0+/-2.1 years) and 28 control subjects (16 males, 12 females; 16.9+/-2.3 years). All AUD subjects were recruited from substance abuse treatment programs and had comorbid mental disorders. RESULTS: Subjects with alcohol use disorders had smaller prefrontal cortex and prefrontal cortex white matter volumes compared with control subjects. Right, left, and total thalamic, pons/brainstem, right and left cerebellar hemispheric, total cerebellar, and cerebellar vermis volumes did not differ between groups. There was a significant sex-by-group effect, indicating that males with an adolescent-onset AUD compared with control males had smaller cerebellar volumes, whereas the two female groups did not differ in cerebellar volumes. Prefrontal cortex volume variables significantly correlated with measures of alcohol consumption. CONCLUSIONS: These findings suggest that a smaller prefrontal cortex is associated with early-onset drinking in individuals with comorbid mental disorders. Further studies are warranted to examine if a smaller prefrontal cortex represents a vulnerability to, or a consequence of, early-onset drinking.     

Body mass index is associated with brain metabolite levels in alcohol dependence--a multimodal magnetic resonance study

Background: Recent studies demonstrated that alcohol dependence and excessive alcohol consumption are associated with increased rates of obesity. In healthy light‐drinkers, we and others have observed associations between elevated body mass index (BMI) and reductions in brain volumes, lower concentrations of N‐acetyl‐aspartate (NAA, marker of neuronal viability) and choline‐containing compounds (Cho, involved in membrane turnover), and lower glucose utilization, particularly in frontal lobe—a brain region that is particularly vulnerable to the effects of alcohol dependence. Here, we evaluated whether BMI in alcohol‐dependent individuals was independently associated with regional measures of brain structure, metabolite concentrations, and neocortical blood flow. Methods: As part of a study on the effects of alcohol dependence on neurobiology, we analyzed retrospectively data from 54 alcohol‐dependent males, abstinent from alcohol for about 1 month and with BMI between 20 and 37 kg/m² by structural MRI, perfusion MRI (blood flow), and proton magnetic resonance spectroscopic imaging. Results: After correction for age, smoking status, and various measures of alcohol consumption, higher BMI was associated with lower concentrations of NAA, Cho, creatine and phosphocreatine (Cr, involved in high energy metabolism), and myo‐inositol (m‐Ino, a putative marker of astrocytes) primarily in the frontal lobe, in subcortical nuclei, and cerebellar vermis (p < 0.004). Regional brain volumes and perfusion were not significantly related to BMI. Furthermore, comorbid conditions, clinical laboratory measures, and nutritional assessments were not significant predictors of these MR‐based measures. Conclusions: The results suggest that BMI, independent of age, alcohol consumption, and common comorbidities, is related to regional NAA, Cho, Cr, and m‐Ino concentrations in this cohort of alcohol‐dependent individuals. Additionally, as some common comorbid conditions in alcohol dependence such as cigarette smoking are associated with BMI, their associations with regional brain metabolite levels in alcohol‐dependent individuals may also be influenced by BMI.     

Callosal thickness reductions relate to facial dysmorphology in fetal alcohol spectrum disorders

Background: Structural abnormalities of the corpus callosum (CC), such as reduced size and increased shape variability, have been documented in individuals with fetal alcohol spectrum disorders (FASD). However, the regional specificity of altered CC structure, which may point to the timing of neurodevelopmental disturbances and/or relate to specific functional impairments, remains unclear. Furthermore, associations between facial dysmorphology and callosal structure remain undetermined. Methods: One hundred and fifty‐three participants (age range 8 to 16) including 82 subjects with FASD and 71 nonexposed controls were included in this study. The structural magnetic resonance imaging data of these subjects was collected at 3 sites (Los Angeles and San Diego, California, and Cape Town, South Africa) and analyzed using classical parcellation schemes, as well as more refined surface‐based geometrical modeling methods, to identify callosal morphological alterations in FASD at high spatial resolution. Results: Reductions in callosal thickness and area, specifically in the anterior third and the splenium, were observed in FASD compared with nonexposed controls. In addition, reduced CC thickness and area significantly correlated with reduced palpebral fissure length. Conclusions: Consistent with previous reports, findings suggest an adverse effect of prenatal alcohol exposure on callosal growth and further indicate that fiber pathways connecting frontal and parieto‐occipital regions in each hemisphere may be particularly affected. Significant associations between callosal and facial dysmorphology provide evidence for a concurrent insult to midline facial and brain structural development in FASD.     

Blood oxygen level dependent response and spatial working memory in adolescents with alcohol use disorders

BACKGROUND: Previous studies have suggested neural disruption and reorganization in young and older adults with alcohol use disorders (AUD). However, it remains unclear at what age and when in the progression of AUD changes in brain functioning might occur. METHODS: Alcohol use disordered (n = 15) and nonabusing (n = 19) boys and girls aged 15 to 17 were recruited from local high schools. Functional magnetic resonance imaging data were collected after a minimum of 5 days' abstinence as participants performed spatial working memory and simple motor tasks. RESULTS: Adolescents with AUD showed greater brain response to the spatial working memory task in bilateral parietal cortices and diminished response in other regions, including the left precentral gyrus and bilateral cerebellar areas (clusters > or =943 microl; p < 0.05), although groups did not differ on behavioral measures of task performance. No brain response differences were observed during a simple finger-tapping task. The degree of abnormality was greater for teens who reported experiencing more withdrawal or hangover symptoms and who consumed more alcohol. CONCLUSIONS: Adolescents with AUD show abnormalities in brain response to a spatial working memory task, despite adequate performance, suggesting that subtle neuronal reorganization may occur early in the course of AUD.     

Ventricular expansion in wild-type Wistar rats after alcohol exposure by vapor chamber

Background: Structural magnetic resonance imaging (MRI) reveals widespread brain damage manifest as tissue shrinkage and complementary ventriculomegaly in human alcoholism. For an animal model to parallel the human condition, high alcohol exposure should produce similar radiologically detectable neuropathology. Our previous structural MRI study demonstrated only modest brain dysmorphology of the alcohol‐preferring (P) rat with average blood alcohol levels (BALs) of 125 mg/dl achieved with voluntary consumption. Here, we tested the hypothesis that wild‐type Wistar rats, exposed to vaporized alcohol ensuring higher BALs than typically achieved with voluntary consumption in rodents, would model MRI findings in the brains of humans with chronic alcoholism. Methods: The longitudinal effects of vaporized alcohol exposure on the brains of 10 wild‐type Wistar rats compared with 10 sibling controls were investigated with structural MRI, conducted before (MRI 1) and after (MRI 2) 16 of alcohol exposure and after an additional 8 weeks at a higher concentration of alcohol (MRI 3). Results: Two rats in the alcohol group died prior to MRI 2. The remaining vapor‐exposed rats (n = 8) achieved BALs of 293 mg/dl by MRI 2 and 445 mg/dl by MRI 3. Whereas the controls gained 17% of their body weight from MRI 1 to MRI 3, the alcohol‐exposed group lost 6%. MRI, quantified with atlas‐based parcellation, revealed a profile of significant ventricular expansion, after alcohol vapor exposure, in 9 contiguous slices, extending from the dorsolateral to ventrolateral ventricles. In particular, from MRI 1 to MRI 2, this ventricular volume expanded by an average of 6.5% in the controls and by 27.1% in the alcohol‐exposed rats but only an additional 1.5% in controls and 2.4% in alcohol‐exposed rats from MRI 2 to MRI 3. The midsagittal volume of the full anterior‐to‐posterior extent of the corpus callosum grew between the first 2 MRIs in both groups followed by regression in the alcohol group by MRI 3. Although group differences were statistically significant, among animals there was substantial variability of the effects of alcohol exposure on brain morphology; some animals showed profound effects, whereas others were essentially unaffected. Conclusions: The ventricular dilatation and callosal shrinkage produced in wild‐type rats following involuntary alcohol exposure yielded a modestly successful model of neurodysmorphology phenotypes of human alcoholism. As is the case for the human condition, however, in which some individuals express greater alcoholism‐related neuropathology than others, some rats may be more susceptible than others to extreme alcohol exposure.     

Characterization of South African adolescents with alcohol use disorders but without psychiatric or polysubstance comorbidity

Background: Individuals who begin drinking during early adolescence and exhibit externalizing pathology and disinhibitory/dysregulatory tendencies are more vulnerable to developing alcohol use disorders (AUDs) in adulthood. Previous research has focused on in‐treatment populations with substantial comorbid psychopathology and polysubstance use. Here, we characterize a unique sample of treatment‐naïve adolescents without such comorbidity to help identify vulnerable youth who may benefit from early intervention. Methods: We compared externalizing propensity, disinhibitory characteristics, and school performance in adolescents with AUDs (but without comorbid psychopathology or other substance use; n = 70) to those of demographically matched controls (n = 70). Within the AUD group, we compared measures of substance use and the disinhibitory syndrome between boys and girls with differing severity of externalizing propensity. Results: Adolescents with AUDs demonstrated more externalizing propensity and disinhibitory personality traits (impulsivity, novelty seeking, and excitement seeking), poorer self‐monitoring and response inhibition, more bullying and sexual risk‐taking behavior, poorer first‐language performance, and greater use of alcohol, cannabis, and nicotine (p < 0.05). Within the AUD group, participants with higher externalizing propensity began drinking earlier, more frequently, and for a longer duration than those with lower externalizing symptoms (p < 0.05). Disinhibitory features (personality, cognition, and behavior) were, however, not stronger in those with higher externalizing propensity. Conclusions: We suggest that the constructs of externalizing propensity and disinhibitory syndrome are useful in characterizing treatment‐naïve adolescents with AUDs but without comorbid psychopathology or polysubstance use. These results support the importance of these constructs in understanding adolescent AUDs, even when the frank externalizing diagnoses of childhood (oppositional defiant disorder and conduct disorder) are excluded.     

The contribution of parental alcohol use disorders and other psychiatric illness to the risk of alcohol use disorders in the offspring

Background: Few population‐based studies have investigated associations between parental history of alcoholism and the risk of alcoholism in offspring. The aim was to investigate in a large cohort the risk of alcohol use disorders (AUD) in the offspring of parents with or without AUD and with or without hospitalization for other psychiatric disorder (OPD). Methods: Longitudinal birth cohort study included 7,177 men and women born in Copenhagen between October 1959 and December 1961. Cases of AUD were identified in 3 Danish health registers and cases of OPD in the Danish Psychiatric Central Register. Offspring registration with AUD was analyzed in relation to parental registration with AUD and OPD. Covariates were offspring gender and parental social status. Results: Both maternal and paternal registration with AUD significantly predicted offspring risk of AUD (odds ratios 1.96; 95% CI 1.42 to 2.71 and 1.99; 95% CI 1.54 to 2.68, respectively). The association between maternal, but not paternal, OPD and offspring AUD was also significant (odds ratios 1.46; 95% CI 1.15 to 1.86 and 1.26; 95% CI 0.95 to 1.66, respectively). Other predictors were male gender and parental social status. A significant interaction was observed between paternal AUD and offspring gender on offspring AUD, and stratified analyses showed particularly strong associations of both paternal and maternal AUD with offspring AUD in female cohort members. Conclusions: Parental AUD was associated with an increased risk of offspring AUD independent of other significant predictors, such as gender, parental social status, and parental psychiatric hospitalization with other diagnoses. Furthermore, this association appeared to be stronger among female than male offspring. The results suggest that inherited factors related to alcoholism are at least as important in determining the risk of alcoholism among daughters as among sons.