Now showing items 1-20 of 201

    • Charting Neurotypical Change in Complement and Cytokine Levels Across Postnatal Human Cortical Development

      Sager, Rachel (2021-12)
      A burgeoning body of evidence supports a role for immune signals in neurotypical human brain development. Furthermore, associations between neuroinflammation in development and the subsequent increased risk for psychiatric disorders indicate that an excess of immune signaling early in life damages brain function later in life. In this dissertation, I examined the postnatal expression of two major immune signaling families: complement and cytokines; and the relative contributions of neural cell types to the cortical transcriptome. I used high-throughput microarray, quantitative reverse transcription PCR, immunohistochemistry and multiplex immunoassays. I found coordinated increases in glial cell marker, complement, and cytokine transcripts from birth until the typical age of entry into school (age 5). There were two main patterns of change in gene expression encoding immune signals and their receptors: an early postnatal peak in toddlers followed by a decline in expression levels (C1Q, C3, IL-1β, CD11B, IL-1R1, IL-18) and an early postnatal increase in toddlers, followed by additional increases in adolescents and young adults (IL-6, TNF-α). Complement inhibitor mRNAs were also differentially expressed across postnatal human life, increasing before reaching a plateau around school age (CD46, CD55, CR1,) or peaking in young adulthood (SERPING1, CD59). This suggests sustained complement inhibition during adolescence. The multiple cytokine and complement family members that peaked in toddlers suggest a period of dominant immune signaling from age two to five in humans. This may be related to the proliferation or maturation of glia during early postnatal development, whereas the cytokines seen increasing in adolescents and young adults are contemporaneous with periods of proposed increases in synaptic elimination. These findings open up additional avenues of investigation into the role of immune signaling in normal mammalian brain development and support that time periods of normative increases in developmental immune factor signaling overlap with known 'windows of vulnerability' to manifesting autism and schizophrenia.
    • The Role of Laminins in the Retinal Vascular Basement Membrane

      Brunken, William J.; Watters, Jared (2021-11)
      The vascular basement membrane (vBM) of the central nervous system (CNS) is a highly specialized structure that is composed of various extracellular matrix (ECM) proteins and has many functions, including providing a point of adhesion for the cells of the vasculature, serving as a physical barrier, and providing an interface for communication with endothelial cells. One family of ECM molecules, laminins, are responsible for many of these specialized functions. There are 16 known isoforms of laminin, each consisting of a single α, β, and γ-chain. The distribution of these isoforms in the CNS vBM, however, remains unknown. Here, we used the retina to examine the distribution of laminin chains in the CNS vBM throughout development, as well as the roles of β2-containing laminins in vBM organization and γ3-containing laminins in arterial morphogenesis. The results presented in Chapter 2 demonstrate that there are dramatic changes in the temporal and spatial patterning of many of the laminin chains in the retinal vasculature throughout development, particularly the α2, α5, and γ3-chains. We deleted a key component of the CNS vBM, the laminin β2-chain, to gain a deeper understanding of how laminins affect vBM structure. Deletion of the β2-chain leads to decreased expression of several partner chains, including α2, α5, and γ3. Interestingly, the deletion of laminin β2 also leads to increased deposition of two other ECM molecules, agrin and perlecan, in the BMs of retinal veins and arteries, respectively. We also provide strong evidence that astrocytes contribute laminin 221 to the retinal vBM and that this laminin may directly regulate AQP4 expression in vascular associated astrocytic endfeet. The results presented in Chapter 3 demonstrate that laminins are involved in regulating arterial morphogenesis. Specifically, we found that γ3-containing laminins signal through dystroglycan to induce Dll4-Notch signaling, leading to decreased vascular branching and increased smooth muscle coverage: hallmarks of the arterial phenotype. Taken together, the work presented here further elucidates the structural and functional roles for laminins in the CNS vBM.
    • ANALYSIS OF VACUOLAR TYPE - H+ - ATPASE FUNCTION IN NEUROMAST HAIR CELLS IN THE ZEBRAFISH EMBRYO

      Amack, Jeffrey, D.; Santra, Peu (2021-11)
      Vacuolar type H+-ATPase (V-ATPase) is a ubiquitously expressed enzyme complex that pumps protons across membranes. The proton-motive force generated by V-ATPase is used by cells to acidify intracellular compartments. Additionally, certain specialized tissue types have V-ATPase on plasma membranes where it secretes H+into the extracellular space. While V-ATPase activity is essential for several cellular functions, our understanding of cell-type specific functions for V-ATPase remains limited. Here, I focused on investigating V-ATPase functions in mechanosensory hair cells. Hair cells are functional units of mammalian auditory and vestibular systems. Consequently, hair cell loss leads to permanent deafness. Mutation in specific V-ATPase subunits causes sensorineural deafness in human, however, the mechanism is not well understood. I used zebrafish as model vertebrate to investigate how loss of V-ATPase function impacts hair cells. Using a combination of genetic mutations, pharmacological manipulations and live imaging of hair cells in vivo, I found that V-ATPase activity is critical for hair cell survival. Analysis of molecular markers and cellular morphologies indicates hair cells in V-ATPase mutants undergo a caspase-independent, necrosis-like death. V-ATPase mutant hair cells show a significant decrease in mitochondrial membrane potential (mPTP). On modulating mPTP pharmacologically, V-ATPase mutants show a modest but consistent improvement of hair cell survival. These results indicate mitochondrial dysfunction contributes to hair cell death in V-ATPase mutants. Next, I generated a novel cilia pH biosensor and found that hair cell kinocilia have a more basic pH than other primary cilia in zebrafish embryos. Interestingly, my collaborators and I discovered that V-ATPase subunits localize to hair cell kinocilia in zebrafish and mice, which suggests cell-type specific functions for V-ATPase in kinocilia. pH maintenance in kinocilia may be an essential function that contributes to proper kinocilia length and/or function. In conclusion, this work has uncovered a function for V-ATPase activity that is critical for hair cell survival, in part by maintaining mitochondrial health, and a function that mediates hair cell kinocilia form and function. The work presented in this thesis advances our understanding of V-ATPase functioning in hearing loss, more broadly elucidates new in vivo cell-type specific V-ATPase functions.
    • Meta-Analysis of Alzheimer's Disease Risk with Obesity, Diabetes, and Related Disorders

      Profenno, Louis A.; Porsteinsson, Anton P.; Faraone, Stephen V. (Elsevier BV, 2010-03)
      Background: Late-onset Alzheimer’s disease (AD) is a multifactorial and heterogeneous disorder with major risk factors including advanced age, presence of an apolipoprotein E 4 (APOE4) allele, and family history of AD. Other risk factors may be obesity and diabetes and related disorders, which are highly prevalent. Methods: We reviewed longitudinal epidemiological studies of body mass, diabetes, metabolic syndrome, and glucose and insulin levels on risk for AD. We conducted meta-analyses of the results from these studies. Results: For obesity assessed by body mass index, the pooled effect size for AD was 1.59 (95% confidence interval [CI] 1.02–2.5; z 2.0; p .042), and for diabetes, the pooled effect size for AD was 1.54 (95% CI 1.33–1.79; z 5.7; p .001). Egger’s test did not find significant evidence for publication bias in the meta-analysis for obesity (t 1.4, p .21) or for diabetes (t .86, p .42). Since these disorders are highly comorbid, we conducted a meta-analysis combining all studies of obesity, diabetes, and abnormal glucose or insulin levels, which yielded a highly significant pooled effect size for AD of 1.63 (95% CI 1.39 –1.92; z 5.9; p .001). Conclusions: Obesity and diabetes significantly and independently increase risk for AD. Though the level of risk is less than that with the APOE4 allele, the high prevalence of these disorders may result in substantial increases in future incidence of AD. Physiological changes common to obesity and diabetes plausibly promote AD.
    • RASD2, MYH9, and CACNG2 Genes at Chromosome 22q12 Associated with the Subgroup of Schizophrenia with Non-Deficit in Sustained Attention and Executive Function

      Liu, Yu-Li; Fann, Cathy Shen-Jang; Liu, Chih-Min; Chen, Wei J.; Wu, Jer-Yuarn; Hung, Shuen-Iu; Chen, Chun-Houh; Jou, Yuh-Shan; Liu, Shi-Kai; Hwang, Tzung-Jeng; et al. (Elsevier BV, 2008-11)
      Background: In a previous linkage study of schizophrenia that included Taiwanese samples, the marker D22S278 (22q12.3) was significantly linked to schizophrenia (p .001). Methods: We conducted fine mapping of the implicated genomic region, with 47 validated single nucleotide polymorphism (SNP) markers around 1 Mb of D22S278, in a Taiwanese sample of 218 pedigrees with at least 2 siblings affected with schizophrenia. We examined the association of these SNPs and their haplotypes with schizophrenia and with subgroups defined by the presence and absence of deficits in sustained attention as assessed by undegraded and degraded continuous performance tests (CPTs). We also examined subgroups defined by deficits in categories achieved in the Wisconsin Card Sort Test (WCST). Results: Three of five candidate vulnerability genes (RASD2, APOL5, MYH9, EIF3S7, and CACNG2), which had marginally significant associations with schizophrenia, had significant associations with schizophrenic patients who did not have deficits in sustained attention on the undegraded CPT (RASD2 gene SNP rs736212; p .0008 with single locus analysis) and the degraded CPT (MYH9 gene haplotype 1-1-1-1 of SNP rs3752463 - rs1557540 - rs713839 - rs739097; p .0059 with haplotype analysis). We also found a significant association for patients who showed no deficits in executive function as measured by categories achieved in the WCST (CACNG2 gene haplotype 2-1-1-1 of SNP rs2267360 - rs140526 - rs1883987 - rs916269; p .0163 with haplotype analysis). Conclusions: The genes RASD2, MYH9, and CACNG2 might be vulnerability genes for neuropsychologically defined subgroups of schizophrenic patients.
    • Advanced Paternal Age and Early Onset of Schizophrenia in Sporadic Cases: Not Confounded by Parental Polygenic Risk for Schizophrenia

      Wang, Shi-Heng; Hsiao, Po-Chang; Yeh, Ling-Ling; Liu, Chih-Min; Liu, Chen-Chung; Hwang, Tzung-Jeng; Hsieh, Ming H.; Chien, Yi-Ling; Lin, Yi-Ting; Huang, Yen-Tsung; et al. (Elsevier BV, 2019-07)
      BACKGROUND:Whether paternal age effect on schizophrenia is a causation or just an association due to con-founding by selection into late parenthood is still debated. We investigated the association between paternal age andearly onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia asempirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium.METHODS:Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research inTaiwan project, 1649 had parents’genotyping data. The relationships of paternal schizophrenia PRS to paternal ageatfirst birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model ofpatients’early onset of schizophrenia (#18 years old) on paternal age was conducted.RESULTS:Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset ofschizophrenia (odds ratio per 10-year increase in paternal age = 1.28,p= .007) after adjusting for maternal age, sex,and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, aU-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting forboth paternal and maternal schizophrenia PRS, the association of paternal age with patients’early onset ofschizophrenia remained (odds ratio = 1.29,p= .04).CONCLUSIONS:The association between paternal age and early onset of schizophrenia was not confounded byparental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Ourfindingssupport an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring
    • A Twin Study of Sexual Behavior in Men

      Lyons, Michael J.; Koenen, Karestan C.; Buchting, Francisco; Meyer, Joanne M.; Eaves, Lindon; Toomey, Rosemary; Eisen, Seth A.; Goldberg, Jack; Faraone, Stephen V.; Ban, Rachel J.; et al. (Springer Science and Business Media LLC, 2004-04)
      The role of genetic and environmental influences on age of initiation of first sexual relations and engaging in sexual activity with multiple partners (10 or more partners in 1 year) was investigated in male twins (N = 6, 744) from the Vietnam Era Twin Registry. Individual differences in both types of sexual behaviors were heritable, but only age of onset of sexual relations was significantly influenced by the environment shared by the twins. There was a moderate negative correlation between age of initiation of sexual relations and the multiple partners variable; initiating sexual relations earlier was associated with a higher probability of having multiple partners. The additive genetic influence on age of initiation also influenced the multiple partners variable. The substantial unique environmental influences on each variable were uncorrelated with each other. The data suggest that the observed association between age of initiation of sexual relations and having multiple partners is due to genetic influences common to both behaviors.
    • Associations Between ADHD and Psychoactive Substance use Disorders:Findings from a Longitudinal Study of High-Risk Siblings of ADHD Children

      Milberger, Sharon; Biederman, Joseph; Faraone, Stephen V.; Wilens, Timothy; Chu, Monica P. (Wiley, 1997-01)
      The purpose of this study was to determine whether the single nucleotide polymorphisms (SNPs) within candidate genes for attention deficit hyperactivity disorder (ADHD) are associated with the age at onset for ADHD. One hundred and forty-three SNPs were genotyped across five candidate genes (DRD5, SLC6A3, HTR1B, SNAP25, DRD4) for ADHD in 229 families with at least one affected offspring. SNPs with the highest estimated power to detect an association with age at onset were selected for each candidate gene, using a power-based screening procedure that does not compromise the nominal significance level. A time-to-onset analysis for family-based samples was performed on these SNPs to determine if an association exists with age at onset for ADHD. Seven consecutive SNPs surrounding the D5 dopamine receptor gene (DRD5), were associated with the age at onset for ADHD; FDR adjusted q-values ranged from 0.008 to 0.023. This analysis indicates that individuals with the risk genotype develop ADHD earlier than individuals with any other genotype. A haplotype analysis across the 6 significant SNPs that were in linkage disequilibrium with one another, CTCATA, was also found to be significant (p-value = 0.02). We did not observe significant associations with age at onset for the other candidate loci tested. Although definitive conclusions await independent replication, these results suggest that a variant in DRD5 may affect age at onset for ADHD
    • Further evidence of an association between maternal smoking during pregnancy and attention deficit hyperactivity disorder: Findings from a high-risk sample of siblings

      Milberger, Sharon; Biederman, Joseph; Faraone, Stephen V.; Jones, Janice (Informa UK Limited, 1998-09)
      The authors investigated the relationship between attentiondeficit/byperactivity disorder (ADHD) and cigarette smoking in siblings of ADHD and non-ADHD probands. They conducted a 4-year follow-up of siblings from ADHD and control-group families. In the siblings of ADHD probands, ADHD was associated with higher rates and earlier onset of cigarette smoking. There was also a significant positive association between cigarette smoking and conduct disorder, major depression, and drug abuse in the siblings, even after adjusting for confounding variables. Moreover, smoking was found to be familial among ADHD families but not control-group families. Our findings indicate that ADHD is a risk factor for early initiation of cigarette smoking in the high-risk siblings of ADHD probands
    • Substance Use Disorders in High-Risk Adolescent Offspring

      Milberger, Stephen V. Faraone, Jose, Sharon (Wiley, 1999-01)
      Objective: To examine the risk for substance use disorders (SUD) in offspring of SUD parents who were not selected due to referral to SUD treatment centers. Method: The original sample was ascertained through two groups of index children: 140 ADHD probands and 120 non-ADHD comparison probands. These groups had 174 and 129 biological siblings and 279 and 240 parents, respectively. Results: We found that: 1) parental SUD was associated with SUD and all SUD subtypes in the offspring; 2) parental alcohol use disorders were associated with alcohol use disorders in the offspring as well as co-occurring alcohol and drug use disorders but not drug use disorders alone in the offspring; and 3) drug use disorders in the parents were associated with drug use disorders but not alcohol use disorders in the offspring. Conclusions: These findings suggest that alcoholism and drug abuse may breed true from parents to their offspring, but further work with larger samples is needed to confirm this idea. Our findings also suggest a possible common diathesis that is expressed as comorbid alcohol and drug use in the offspring of alcoholic parents. If confirmed, these findings may be useful for the development of preventive and early intervention strategies for adolescents at high risk for SUD based on parental history of SUD.
    • Characteristics of Adults with Attention Deficit Hyperactivity Disorder Plus Substance Use Disorder: The Role of Psychiatric Comorbidity

      Wilens, Timothy E.; Kwon, Anne; Tanguay, Sarah; Chase, Rhea; Moore, Hadley; Faraone, Stephen V.; Biederman, Joseph (Wiley, 2005-01)
      The objective of the study was to investigate the characteristics of adults with Attention Deficit Hyperactivity Disorder (ADHD) or substance use disorder (SUD), especially in the context of comorbid psychiatric disorders. Subjects were adults (n ¼ 78) participating in a controlled family study of ADHD and SUD. Four groups were identified based on a diagnosis of ADHD or SUD: ADHD, SUD, ADHDþSUD, and neither ADHD nor SUD. All diagnoses were determined by structured clinical interview for DSM IV. Rates of psychiatric comorbidity were lowest in the controls, intermediate in the ADHD and SUD groups, and highest in the ADHDþSUD group. Relative to controls, the ADHD, SUD, and ADHDþSUD groups had higher rates of major depression (z ¼ 1.98, p ¼ 0.05), conduct disorder (z ¼ 2.0, p ¼ 0.04), antisocial personality disorder (z ¼ 2.6, p ¼ 0.009), agoraphobia (z ¼ 2.5, p ¼ 0.01) and social phobia (z ¼ 2.7, p ¼ 0.007). Higher rates of psychiatric comorbidity, especially mood and anxiety disorders, exist in subjects with SUDþADHD relative to subjects with SUD, ADHD, or controls. Clinicians need to be attentive to other psychiatric disorders that may occur in the large group of adults with ADHDþSUD.
    • Influence of Parental SUD and ADHD on ADHD in their Offspring: Preliminary Results from a Pilot-controlled Family Study

      Wilens, Timothy E.; Hahesy, Amy L.; Biederman, Joseph; Bredin, Elizabeth; Tanguay, Sarah; Kwon, Anne; Faraone, Stephen V. (Wiley, 2005-03)
      As part of a pilot-controlled family-based study of the children of parents with and without substance use disorders (SUD), the influence of parental SUD and ADHD on the risk for ADHD in offspring was evaluated. Using structured psychiatric interviews, 96 families (183 youth; mean age 11.6 years) were assessed. To evaluate the effect of parental ADHD and SUD, the offspring were stratified into four groups based on parental status: children of parents with neither ADHD nor SUD, children of parents with SUD only, children of parents with ADHD only, and children of parents with both ADHD and SUD. Using generalized estimating equation models, parental SUD and ADHD were used to predict ADHD in the offspring. The rate of children with ADHD increased among children of parents with neither disorder (3%), children of parents with SUD (13%), children of parents with ADHD (25%), and children of parents with both ADHD and SUD (50%) (p ¼ :001). Children of parents with ADHD or ADHD plus SUD were more likely to have ADHD in comparison to children of parents with neither diagnosis (p < 0:05). Children of parents with ADHD plus SUD were at greater risk of ADHD in comparison to children of parents with SUD only (p ¼ 0:01). Despite the small sample size, the results of this study seem to suggest that the offspring of SUD or ADHD parents are at elevated risk for ADHD compared to controls. The offspring of parents with both ADHD and SUD appear to be at the highest risk for ADHD, highlighting the need for careful screening of this group of youth for ADHD. Replication studies clarifying the nature and strength of the association are necessary.
    • Substance Use among ADHD Adults: Implications of Late Onset and Subthreshold Diagnoses

      Faraone, Stephen V.; Wilens, Timothy E.; Petty, Carter; Antshel, Kevin; Spencer, Thomas; Biederman, Joseph (Wiley, 2007-01)
      Diagnosing ADHD in adults is difficult when the diagnostician cannot establish an onset prior to the DSM-IV criterion of age seven or if the number of symptoms does not achieve the DSM threshold for diagnosis. These diagnostic issues are an even larger concern for clinicians faced with adults with substance use disorders (SUD). The present study compared four groups of adults: full ADHD subjects who met all DSM-IV criteria for childhood onset ADHD, late onset ADHD subjects who met all criteria except the age at onset criterion, subthreshold ADHD subjects who did not meet full symptom criteria, and nonADHD subjects who did not meet any of the above criteria. Diagnoses were by the Structured Clinical Interview for DSM-IV, and the Drug Use Severity Index (DUSI) was used for self-report of substance use. Cigarette and marijuana use was significantly greater in all ADHD groups relative to non-ADHD controls. Although usage rates of other drugs failed to reach significance, the ADHD groups were more likely to have used each drug (except alcohol) compared with the non-ADHD group. The late onset and full ADHD groups were more likely to have endorsed ever having a problem due to use of cigarettes, alcohol, or marijuana and reported more trouble resisting use of drugs or alcohol. The full ADHD group was more likely than the other groups to have reported ‘‘getting high’’ as their reason for using their preferred drug. Adults with ADHD have elevated rates of substance use and related impairment. Data about late onset ADHD provides further support for the idea that the DSM-IV age at onset criterion is too stringent. In contrast, subthreshold ADHD seems to be a milder form of the disorder, or perhaps a heterogeneous group of true ADHD cases and false positives.
    • Psychoactive substance use disorders in adults with attention deficit hyperactivity disorder (ADHD): effects of ADHD and psychiatric comorbidity

      Biederman, J; Wilens, T; Mick, E; Milberger, S; Spencer, T J; Faraone, Stephen V. (American Psychiatric Association Publishing, 1995-11)
      Objective: The authors evaluated the association between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorders in adults with ADHD, attending to comorbidity with mood, anxiety, and antisocial disorders. It was hypothesized that psychiatric comorbidity would be a risk factor for psychoactive substance use disorders. Method: Findings for 120 referred adults with a clinical diagnosis ofchildhood-onset ADHD were compared with those for non-ADHD adult comparison subjects (N=268). All childhood and adult diagnoses were obtained by structured psychiatric interviews for DSM-III-R. Rı ıiiIt.ıi There was a significantly higher lifetime risk for psychoactive substance use disorders in the ADHD adults than in the comparison subjects (52% versus 27%). Although the two groups did not differ in the rate ofalcohol use disorders, the ADHD adults had significantly higher rates ofdrug and drug plus alcohol use disorders than the comparison subjects. ADHD significantly increased the risk for substance use disorders independently ofpsychiatric comorbidity. Antisocial disorders significantly increased the risk for substance use disorders independently ofADHD status. Mood and anxiety disorders increased the risk for substance use disorders in both the ADHD and comparison subjects, but more demonstrably in the comparison subjects. Conclusions: Although psychiatric comorbidity increased the risk for psychoactive substance use disorders in adults with ADHD, by itself ADHD was a significant risk factor for substance use disorders. More information is needed to further delineate risk and protective factors mediating the development of substance use disorders in persons with ADHD.
    • Six-week, double-blind, placebo-controlled study of desipramine for adult attention deficit hyperactivity disorder

      Wilen, T E; Biederman, J; Prince, J; spencer, T J; Faraone, Stephen V.; Warburton, R; Schleifer, D; Harding, M; Linehan, C; Geller, D (American Psychiatric Association Publishing, 1996-09)
      O bjective: The factor structures of individual positive and negative symptoms as well as global ratings were examined in a diagnostically heterogeneous group of subjects. Method: Subjects were identified through a clinical and family study of patients with major psychoses at a VA medical center and evaluated with the Scale for the Assessment of N egative Symptoms and the Scale for the Assessment of Positive Symptoms. For the examination of global-level factor structures (N =630), both principal-component analysis and factor analysis with orthogonal rotation were used. Factor analysis was used for the examination of item-level factor structures as well (N =549). Results: The principal-component analysis of global ratings revealed three factors: negative symptoms, positive symptoms, and disorganization. The factor analysis of global ratings revealed a negative symptom factor and a positive symptom factor. The itemlevel factor analysis revealed two negative symptom factors (diminished expression and disordered relating), two positive symptom factors (bizarre delusions and auditory hallucinations), and a disorganization factor. Conclusions: The generation of additional meaningful factors at the item level suggests that important information about symptoms is lost when only global ratings are viewed. Future work should explore clinical and pathological correlates of the more differentiated item-level symptom dimensions
    • Revisiting the factor structure for positive and negative symptoms: evidence from a large heterogeneous group of psychiatric patients

      Toomey, R; Kremen, W S; simpson, J C; Samson, J A; Seidman, L J; Lynons, M J; Faraone, Stephen V.; Tsuang, M T (American Psychiatric Association Publishing, 1997-03)
      O bjective: The factor structures of individual positive and negative symptoms as well as global ratings were examined in a diagnostically heterogeneous group of subjects. Method: Subjects were identified through a clinical and family study of patients with major psychoses at a VA medical center and evaluated with the Scale for the Assessment of N egative Symptoms and the Scale for the Assessment of Positive Symptoms. For the examination of global-level factor structures (N =630), both principal-component analysis and factor analysis with orthogonal rotation were used. Factor analysis was used for the examination of item-level factor structures as well (N =549). Results: The principal-component analysis of global ratings revealed three factors: negative symptoms, positive symptoms, and disorganization. The factor analysis of global ratings revealed a negative symptom factor and a positive symptom factor. The itemlevel factor analysis revealed two negative symptom factors (diminished expression and disordered relating), two positive symptom factors (bizarre delusions and auditory hallucinations), and a disorganization factor. Conclusions: The generation of additional meaningful factors at the item level suggests that important information about symptoms is lost when only global ratings are viewed. Future work should explore clinical and pathological correlates of the more differentiated item-level symptom dimensions
    • Dopamine D4 Gene 7-Repeat Allele and Attention Deficit Hyperactivity Disorder

      Faraone, Stephen V.; Biederman, Joseph; Weiffenbach, Barbara; Keith, Tim; Chu, Monica P.; Weaver, Alix; Spencer, Thomas J.; Wilens, Timothy E.; Frazier, Jean; Cleves, Mario; et al. (American Journal of Psychiatry, 1999-05)
      Objective: Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component, and some studies have reported an association between ADHD and the dopamine D4 (DRD4) gene. Method: The authors recruited 27 triads that comprised an ADHD adult, his or her spouse, and their ADHD child. These triads were assessed for ADHD, and their DNA was genotyped for DRD4 alleles. Results: A multiallelic transmission disequilibrium test suggested an association between ADHD and the DRD4 7-repeat allele. Among family members, the number of 7-repeat alleles predicted the diagnosis of ADHD. Conclusions: Prior reports of an association between ADHD and DRD4 generalize to families recruited through clinically referred ADHD adults. However, because there are some conflicting studies, further work is needed to clarify the role of DRD4 in the etiology of the disorder.
    • Age-Dependent Decline of Symptoms of Attention Deficit Hyperactivity Disorder: Impact of Remission Definition and Symptom Type

      Biederman, J. (American Psychiatric Association Publishing, 2000-05-01)
      Objective: Symptom decline in attention deficit hyperactivity disorder (ADHD) was examined with different definitions of remission. Method: Symptoms in 128 boys were measured five times over 4 years. The prevalences of syndromatic (less than full syndrome), symptomatic (less than subthreshold diagnosis), and functional (full recovery) remission were estimated as a function of age with multivariate logistic regression. Results: Age was significantly associated with decline in total ADHD symptoms and symptoms of hyperactivity, impulsivity, and inattention. Symptoms of inattention remitted for fewer subjects than did symptoms of hyperactivity or impulsivity. The proportion of subjects experiencing remission varied considerably with the definition used (highest for syndromatic remission, lowest for functional remission). Conclusions: These results indicate that differences in reported remission rates reflect the definition used rather than the disorder’s course. They provide systematic support for the clinical observation that hyperactivity and impulsivity symptoms tend to decline at a higher rate than inattention symptoms.
    • A Controlled Study of Behavioral Inhibition in Children of Parents With Panic Disorder and Depression

      Rosenbaum, Jerrold F.; Biederman, Joseph; Hirshfeld-Becker, Dina R.; Kagan, Jerome; Snidman, Nancy; Friedman, Deborah; Nineberg, Allan; Gallery, Daniel J.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2000-12)
      Objective: “Behavioral inhibition to the unfamiliar” has been proposed as a precursor to anxiety disorders. Children with behavioral inhibition are cautious, quiet, introverted, and shy in unfamiliar situations. Several lines of evidence suggest that behavioral inhibition is an index of anxiety proneness. The authors sought to replicate prior findings and examine the specificity of the association between behavioral inhibition and anxiety. Method: Laboratory-based behavioral observations were used to assess behavioral inhibition in 129 young children of parents with panic disorder and major depression, 22 children of parents with panic disorder without major depression, 49 children of parents with major depression without panic disorder, and 84 children of parents without anxiety disorders or major depression (comparison group). A standard definition of behavioral inhibition based on previous research (“dichotomous behavioral inhibition”) was compared with two other definitions. Results: Dichotomous behavioral inhibition was most frequent among the children of parents with panic disorder plus major depression (29% versus 12% in comparison subjects). For all definitions, the univariate effects of parental major depression were significant (conferring a twofold risk for behavioral inhibition), and for most definitions the effects of parental panic disorder conferred a twofold risk as well. Conclusions: These results suggest that the comorbidity of panic disorder and major depression accounts for much of the observed familial link between parental panic disorder and childhood behavioral inhibition. Further work is needed to elucidate the role of parental major depression in conferring risk for behavioral inhibition in children.