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R D Todd

Publications and source records attributed to R D Todd.

At least 37 records · Page 2Linked to original sources
PubMed2000

Reciprocal social behavior in children with and without pervasive developmental disorders.

An invariant feature of pervasive developmental disorders (PDDs) is a relative deficit in the capacity for reciprocal social behavior (RSB). The authors acquired teacher reports of RSB in 287 schoolchildren and parent reports of RSB in 158 child psychiatric patients using a new research instrument, the Social Reciprocity Scale. Total scores on this measure of RSB were continuously distributed in all groups of subjects; children with PDDs scored significantly higher for the degree of deficits in RSB than did clinical or nonclinical controls. Latent class analysis and factor analysis failed to demonstrate separate categories of deficiency for core autistic symptomatology and more general impairments in RSB, consistent with the notion of a "broader autism phenotype." Assessments of RSB on a continuous scale may be useful clinically for characterizing the behavior of children whose social deficits fall below the threshold for a full diagnosis of autism. They may also be useful in genetic-linkage studies of autistic spectrum disorders.

Adolescent↗
PubMed2000

Genetic structure of reciprocal social behavior.

OBJECTIVE: The study examined the genetic structure of deficits in reciprocal social behavior in an epidemiologic sample of male twins. METHOD: Parents of 232 pairs of 7-15-year-old male twins completed the Social Reciprocity Scale to provide data on their children's reciprocal social behavior. Scale scores were analyzed by using structural equation modeling. RESULTS: Intraclass (twin-twin) correlations for scores on the Social Reciprocity Scale were 0.73 for monozygotic twins (N=98 pairs) and 0.37 for dizygotic twins (N=134 pairs). The best fitting model of causal influences on reciprocal social behavior incorporated additive genetic influences and unique environmental influences. CONCLUSIONS: For school-age boys in the general population, reciprocal social behavior is highly heritable, with a genetic structure similar to that reported for autism in clinical samples. Continuous measures of reciprocal social behavior may be useful for characterizing the broader autism phenotype and may enhance the statistical power of genetic studies of autism.

Adolescent↗
PubMed1999

No difference between platelet serotonin--5-HT(2A) receptors from children with and without ADHD.

To further investigate the possible function of the serotonergic system in the pathophysiology of attention deficit hyperactivity disorder (ADHD), platelet serotonin 5-HT2A receptors were characterized for 19 ADHD children and 17 age-matched control subjects. Subjects were evaluated using the Diagnostic Interview for Children and Adolescents (DICA-R-C)-DSM IV and the Children's Depression Inventory. An aggressive subgroup was also determined by the presence of two or more positive aggressive symptoms on either subjects' or parents' reports. Platelets were isolated from venous blood and 5-HT2A receptor number, and affinity was determined using 125I-LSD binding. There was no difference in platelet 5-HT2A receptor binding characteristics between the two groups. The results from this pilot study suggest a limited function of 5-HT2A receptors in the pathophysiology of ADHD and extend the findings of other previous negative studies of the peripheral serotonergic system in ADHD.

Adolescent↗
PubMed1999

Evaluation of ADHD typology in three contrasting samples: a latent class approach.

OBJECTIVE: To identify subtypes of attention-deficit/hyperactivity disorder (ADHD) and characterize them as either categorical or continuous; to investigate familial resemblance for ADHD among sibling pairs; and to test the robustness of all results by using contrasting data sets. METHOD: Latent class analysis was applied to the ADHD symptom profiles obtained from parents or best informant about their offspring in 3 samples: a population-based set of female adolescent twins (724 monozygotic pairs, 594 dizygotic pairs) and male (N = 425) and female (N = 430) child and adolescent offspring ascertained from high-risk alcoholic families. RESULTS: Latent class analysis revealed 2 categories of clinically significant ADHD which were replicated in all 3 study groups: a subtype with high endorsements of ADHD inattention symptoms and a second combined type with high endorsements of both inattention and hyperactivity-impulsivity items. Both appeared to be continuous across all 3 data groups. The high-risk families contained a class in which members heavily endorsed the ADHD "fidget" item but not other ADHD items. A large proportion of the monozygotic sibs (80%) versus a smaller proportion of dizygotic sibs (52%) were assigned to the same latent class. Among the high-risk children and adolescents, 51% of the female and 41% of the male siblings were concordant for class membership. CONCLUSIONS: The pattern of latent classes suggested that ADHD consists of an inattentive and a combined subtype, within each of which lies a dimensional domain. These analyses further support that genetic factors are significant determinants of latent class membership.

Adolescent↗
PubMed1998

Association analysis in an evolutionary context: cladistic analysis of the DRD2 locus to test for association with alcoholism.

Previous studies testing the dopamine D2 receptor (DRD2) locus for association with alcoholism have produced conflicting results. Failure to screen controls for substance abuse and failure to assess alcoholics for severity have been proposed as causes for the inability of some studies to detect an association. We have reevaluated the involvement of DRD2 mutations in susceptibility to alcoholism with a cladistics-based association analysis after restricting an alcoholic sample to more severe cases. For the present study we tested 55 alcoholic probands and 80 normal controls for differences in the frequency of six haplotypes at the DRD2 locus. The haplotypes were derived from five di-allelic polymorphisms spanning all but the first exon of the DRD2 gene. A cladogram constructed from the haplotypes provided the evolutionary context for a nested statistical analysis. We found no significant evidence for association of the DRD2 haplotypes analyzed with the more severe alcoholic phenotype.

Alcoholism↗
PubMed1998

Mutational and biochemical analysis of dopamine in dystonia: evidence for decreased dopamine D2 receptor inhibition.

The dystonias are a group of serious movement disorders characterized by involuntary muscle spasms of different parts of the body. We recently proposed that hypofunction of dopamine D2 receptor-mediated inhibition of the indirect output pathway of the basal ganglia can result in dystonia. In this review, we discuss the results of a variety of genetic and biochemical studies in light of this hypothesis. Several forms of early-onset dystonia show distinct autosomal dominant, recessive, or X-linked genetic transmission patterns. Late onset forms of dystonia, though not showing clear Mendelian transmission patterns, also appear to be highly familial. Recently, several genetic-linkage locations have been identified for early-onset dystonia and for two of these loci, mutations decreasing dopamine synthesis have been demonstrated. Biochemical studies of monkeys and man also demonstrate that several types of dystonia occur in a dopamine-deficiency state. Similarly, mice strains developed to be deficient in several dopamine-pathway components have motor abnormalities consistent with dystonia. Hypofunction of the dopamine D2 receptor-mediated inhibition of the indirect output pathway of the putamen may be a common feature of many of these heritable and secondary dystonic syndromes.

Animals↗
PubMed1998

Latent class and factor analysis of DSM-IV ADHD: a twin study of female adolescents.

OBJECTIVE: In an attempt to validate the current DSM-IV criteria for attention-deficit/hyperactivity disorder (ADHD) in females and to determine whether symptoms are continuously distributed or categorically discrete, the authors performed factor and latent class analysis on ADHD symptom data from a large general population of adolescent female twins (1,629 pairs). METHOD: A structured diagnostic assessment of DSM-IV ADHD was completed with at least one parent of 1,629 pairs by telephone. ADHD symptoms from 1,549 pairs were subjected to latent class and factor analysis. RESULTS: Latent class and factor analyses were consistent with the presence of separate continuous domains of inattention (ATT), hyperactivity-impulsivity (H-I), and combined ATT with H-I problems. Severe latent classes corresponding to the predominantly inattentive, predominantly hyperactive-impulsive, and combined types were identified with lifetime prevalence estimates of 4.0%, 2.2%, and 3.7%, respectively. Membership in the severe ATT class predicted academic problems, family problems, and referral to health care providers. Membership in the H-I and combined classes also predicted impaired social relationships. CONCLUSIONS: These results suggest that DSM-IV ADHD subtypes can be thought of as existing on separate continua of inattention, hyperactivity-impulsivity, and combined type problems. Membership in any of there severe ADHD latent classes did not preclude academic excellence, but it was associated with different types of impairment and health care-seeking behavior. These data have implications in the areas of diagnosis, classification, treatment, and research.

Adolescent↗
PubMed1998

The unified biosocial model of personality in schizophrenia families and controls.

This report describes the application of a unified biosocial model of personality developed by C.R. Cloninger to a sample of families identified through a proband with schizophrenia and a sample of controls. Families of schizophrenic patients were ascertained in USA and Austria. We could detect differences between females and males in their response to positive reinforcement (Reward Dependence) and differences between young and old people with respect to the response to new and/or exciting situations (Novelty Seeking). In general, results obtained for individuals from schizophrenia families and controls were similar. These results are not substantially influenced by psychiatric disorders in individuals. Psychiatric diagnosis may have an influence on the third dimension of Cloninger's model, designated Harm Avoidance. Analysis showed that patients with a diagnosis of schizophrenia or from the schizophrenia spectrum try harder to avoid punishment or aversive stimuli than family members with another psychiatric disorder or without a psychiatric diagnosis as well as controls. The results are promising and further research is needed to evaluate the structure of the proposed personality model in families and the relationship of personality to psychiatric status.

Adult↗
PubMed1997

Identification of cell type-specific promoter elements associated with the rat tyrosine hydroxylase gene using transgenic founder analysis.

Transcriptional regulatory elements capable of directing transgene expression to individual cells are powerful tools for manipulating a given CNS circuit. Delineating these elements via traditional transgenic analysis is both costly and labor intensive. Here we have used the rat tyrosine hydroxylase (TH) promoter as a model to describe and validate the use of founder animals for systematic promoter studies. No significant differences were found when data obtained from founder animals expressing a 6.0 kb TH promoter directing LacZ were compared with animals derived from an analogous transgenic line. Subsequent studies with founder animals expressing beta-galactosidase directed by various lengths of rat TH promoter revealed different patterns of expression. Specifically, a locus coeruleus regulatory domain was localized between 3.4 and 6.0 kb of the rat TH promoter, a hypothalamic regulatory domain between 2.5 and 3.4 kb and a brainstem regulatory domain between 0.8 and 6.0 kb. At least one element of a midbrain specific regulatory domain was within 2.5 kb of the transcriptional start site. Olfactory bulb specific elements however appeared to reside outside of the sequences tested. Specific patterns of ectopic gene expression were also observed suggesting the presence of negative regulatory elements. Thus, TH appears to be regulated in a complex modular fashion by both positive and negative regulatory elements. Taken together, this study demonstrates the feasibility and reliability of founder analysis for promoter studies of genes expressed in complex spatial and temporal patterns.

Animals↗
PubMed1997

Genetic association between monoamine oxidase and manic-depressive illness: comparison of relative risk and haplotype relative risk data.

There have been several conflicting reports of association of monoamine oxidase (MAO) A gene polymorphisms and bipolar affective disorder. In order to determine the possible role of the MAO region in susceptibility to affective disorders in an independent sample, we have genotyped 83 probands of bipolar affective disorder families, 56 sets of parents of bipolar probands, and 84 normal controls for intronic simple sequence repeat polymorphisms of the MAO-A and MAO-B genes. For MAO-A there were no significant differences in allele frequencies between bipolar and normal control groups for both genders. However, for MAO-B there were significant differences between groups for both genders. In contrast, allele-wise haplotype relative risk analysis for the 56 bipolar proband-parent trios found no significant differences between transmitted and non-transmitted allele frequencies for MAO-A or B. These data do not support the association of MAO-A or B with bipolar affective disorder but do demonstrate that undetected population stratification can be an important source of bias in case-control studies.

Alleles↗
PubMed1997

The rat D4 dopamine receptor couples to cone transducin (Galphat2) to inhibit forskolin-stimulated cAMP accumulation.

Based on its expression pattern and pharmacology, the D4 dopamine receptor may play a role in schizophrenia. Thus it is of interest to know what signaling pathways are utilized by this receptor. Previously, we showed that activation of D4 receptors in a mouse mesencephalic neuronal cell line (MN9D) inhibited forskolin-stimulated cAMP accumulation in a pertussis toxin-sensitive (Ptx-sensitive) fashion. Of the known Ptx-sensitive G-protein alpha subunits, MN9D-expressed Galphai2, GalphaoA, and GalphaoB; however, none of these coupled to the D4 receptor. Using a low stringency polymerase chain reaction cloning method, we found an additional Ptx-sensitive G-protein cone transducin (Galphat2) expressed in the MN9D cells. We also found that Galphat2 mRNA is highly expressed in rat mesencephalic tissue. To test the hypothesis that the D4 receptor couples to Galphat2, we cotransfected MN9D cells with the D4 receptor and a mutagenized Ptx-resistant Galphat2 subunit (mGalphat2). Application of the dopaminergic agonist quinpirole to cotransfected cells inhibited forskolin-stimulated cAMP accumulation in the presence or absence of Ptx. To our knowledge, this is the first report demonstrating that the D4 dopamine receptor functionally couples to a specific G-protein and that a non-opsin-like receptor can couple with a transducin subunit.

Animals↗
PubMed1997

Cladistic analysis of disease association with tyrosine hydroxylase: application to manic-depressive disease and alcoholism.

We evaluated the involvement of tyrosine hydroxylase (TH) mutations in susceptibility to manic-depressive disease (MDD) and alcoholism (ALC) with a cladistics-based association analysis. Eighty-one probands with MDD, 113 probands with alcoholism, and 80 normal controls were tested for differences in frequency of nine haplotypes at the TH locus. The haplotypes were comprised of four restriction fragment length polymorphisms spanning the TH gene. A cladogram constructed from the haplotypes provided the evolutionary context for a nested statistical analysis. Statistically significant evidence was found for association of a subgroup of the sample for each of the disorders with different branches of the gene tree, but the findings were sensitive to minor changes in estimated haplotype frequencies.

Alcoholism↗
PubMed1997

Subgenual prefrontal cortex abnormalities in mood disorders.

Pathological disturbances of mood may follow a 'bipolar' course, in which normal moods alternate with both depression and mania, or a 'unipolar' course, in which only depression occurs. Both bipolar and unipolar disorders can be heritable illnesses associated with neurochemical, neuroendocrine and autonomic abnormalities. The neurobiological basis for these abnormalities has not been established. Using positron emission tomographic (PET) images of cerebral blood flow and rate of glucose metabolism to measure brain activity, we have now localized an area of abnormally decreased activity in the prefrontal cortex ventral to the genu of the corpus callosum in both familial bipolar depressives and familial unipolar depressives. This decrement in activity was at least partly explained by a corresponding reduction in cortical volume, as magnetic resonance imaging (MRI) demonstrated reductions in the mean grey matter volume in the same area of 39 and 48% in the bipolar and unipolar samples, respectively. This region has previously been implicated in the mediation of emotional and autonomic responses to socially significant or provocative stimuli, and in the modulation of the neurotransmitter systems targeted by antidepressant drugs.

Adult↗
PubMed1997

Increased prevalence and earlier onset of mood disorders among relatives of prepubertal versus adult probands.

OBJECTIVE: To compare the familial clustering of affective disorders among first-degree relatives of prepubertal versus adult probands with mood disorders. METHOD: The Family History-Research Diagnostic Criteria (FH-RDC) assessment instrument was used to obtain data on first-degree relatives of all probands. Logistic regression was used to assess the strength of the age of the proband to predict FH-RDC diagnoses in relatives. Survival analysis was used to examine the age-at-onset distribution of first FH-RDC diagnosis while controlling for year of birth. RESULTS: The prevalence of major affective disorders was more than two times higher among first-degree relatives of child probands versus those of adult probands even when controlling for birth cohort. Cumulative risk for lifetime major mood disorders in first-degree relatives of child probands was significantly higher than for those of adult probands. CONCLUSION: These analyses further support that ascertainment of families through affected children identifies pedigrees with a higher proportion of affected relatives than ascertainment through affected adults.

Adult↗
PubMed1997

MPTP induces dystonia and parkinsonism. Clues to the pathophysiology of dystonia.

The pathophysiology of dystonia is unclear, but several clues implicate striatal dopamine dysfunction. In contrast, the causal relationship between striatal dopamine deficiency and parkinsonism is well defined. We now suggest that parkinsonism or dystonia may occur following striatal dopamine deficiency. Baboons treated with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed transient hemidystonia prior to hemiparkinsonism. The day after MPTP treatment, most animals had spontaneous ipsilateral turning. Within a few days, all developed contralateral hemidystonia, with the arm and leg extended and externally rotated. This transient dystonia preceded hemiparkinsonism with flexed posture, bradykinesia, and postural tremor that persisted for up to 1.5 years. Dystonia corresponded temporally with a decreased striatal dopamine content and a transient decrease in D2-like receptor number. The time course of dystonia and parkinsonism is analogous to lower limb dystonia as the first, frequently transient, symptom of Parkinson's disease in humans. The association of striatal dopamine deficiency with dystonia and parkinsonism implies that other factors influence clinical manifestations.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

A linkage map of chromosome 6 based on 2 large kindreds segregating bipolar affective disorder.

Twenty-eight markers, both simple sequence repeats (SSRs) and restriction fragment length polymorphisms (RFLPs), were genotyped on members of 2 large pedigrees (OOA, BIP167) segregating bipolar affective disorder. Using the multipoint program "build" of CRIMAP and odds of placement 1000:1, a unique sex-averaged map was generated that spans 227 cM and includes 26 markers. The two other markers were placed on the map with a lower likelihood. The female recombination map is larger than the male recombination map by about 80%. Linkage analysis between the polymorphisms and the disease in the OOA screening pedigree did not result in any significantly positive lod scores nor did a non-parametric, identity-by-descent, method generate any significant p-values. BIP167 was analyzed for allele sharing at the simple sequence repeat loci and significant associations were not found. At present we conclude, that the pedigrees under study do not have a major predisposition gene for bipolar affective disorder on chromosome 6 under the diagnostic and transmission models analyzed by the 2 different methods.

Bipolar Disorder↗
PubMed1996

Dynamic changes in striatal dopamine D2 and D3 receptor protein and mRNA in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) denervation in baboons.

Loss of nigrostriatal neurons leads to striatal dopamine deficiency and subsequent development of parkinsonism. The effects of this denervation on D2-like receptors in striatum remain unclear. Most studies have demonstrated increases in striatal dopamine D2-like receptors in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated denervation, but others have found either decreases or no change in binding. To clarify the response to denervation, we have investigated the time-dependent changes in dopamine D2, D3, and D4 receptor protein and mRNA levels in unilaterally MPTP-lesioned baboons. MPTP (0.4 mg/kg) was infused into one internal carotid artery, producing a contralateral hemi-parkinsonian syndrome. After MPTP treatment, the animals were maintained for 17-480 d and then euthanized. MPTP decreased ipsilateral dopamine content by >90%, which did not change with time. Ipsilateral D2-like receptor binding in caudate and putamen initially decreased then increased two- to sevenfold over the first 100 d and returned to near baseline levels by 480 d. Relative levels of D2 mRNA were essentially unchanged over this period. D4 mRNA was not detected. In contrast, D3 mRNA increased sixfold by 2 weeks and then decreased. At the peak period of increase in binding sites, all D2-like receptors were in a micromolar affinity agonist-binding state, implying an increase in uncoupled D2 but not D3 receptor protein. Taken together, these data suggest that MPTP-induced changes in D2-like dopamine receptors are complex and include translational or post-translational mechanisms.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗