Biomedical subjects

T D Cannon

Publications and source records attributed to T D Cannon.

At least 37 records · Page 2Linked to original sources

PubMed1999

A prospective cohort study of neurodevelopmental processes in the genesis and epigenesis of schizophrenia.

A number of lines of evidence converge in implicating neurodevelopmental processes in the etiology and epigenesis of schizophrenia. In this study we used a prospective, longitudinal design to examine whether adverse obstetric experiences predict schizophrenia and whether there is a deviant functional-developmental trajectory during the first 7 years of life among individuals who manifest schizophrenia as adults. The 9,236 members of the Philadelphia cohort of the National Collaborative Perinatal Project were screened for mental health service utilization in adulthood, and chart reviews were performed to establish diagnoses according to DSM-IV criteria. The risk for schizophrenia increased linearly with the number of hypoxia-associated obstetric complications but was unrelated to maternal infection during pregnancy or fetal growth retardation. Preschizophrenic cases (and their unaffected siblings who were also cohort members) manifested cognitive impairment, abnormal involuntary movements and coordination deficits, and poor social adjustment during childhood. There was no evidence of intraindividual decline in any domain, but preschizophrenic cases did show deviance on an increasing number of functional indicators with age. Together, these findings suggest that both genetic and obstetric factors participate in creating a neural diathesis to schizophrenia, the phenotypic expressions of which are age dependent, probably reflecting the maturational status of a number of interconnected brain systems.

Adult↗

PubMed1999

Possible association between schizophrenia and a CAG repeat polymorphism in the spinocerebellar ataxia type 1 (SCA1) gene on human chromosome 6p23.

The gene for spinocerebellar ataxia type 1 (SCA1) is a potential candidate gene for schizophrenia because of previous positive linkage findings in this region (6p22-24), and because the reported correlation between SCA1 onset and the number of CAG repeats suggests anticipation. To test the involvement of this gene in the development of schizophrenia, we examined genotypes of the SCA1 CAG repeat polymorphism for 49 Caucasian patients with schizophrenia, and 88 Caucasian controls. We found a significant association between the frequencies of alleles of this gene and schizophrenia (chi 2 = 18.40, df = 8, P = 0.018). Among 13 alleles, one allele (31 trinucleotide repeat) was significantly more frequent in patients with schizophrenia than in controls (chi 2 = 9.57, df = 1, P = 0.002). This association was sustained after applying a Bonferroni correction for multiple testing (P = 0.05/13 = 0.004), and the chi-square results were shown to be robust through Monte Carlo simulation. We observed no allelic association with three flanking microsatellite markers (D6S288, D6S1605, and D6S337), suggesting that our result was not due to population stratification. Further studies of this locus are needed to confirm this finding, and to determine a potential role for this gene in the development of schizophrenia.

Ataxin-1↗

PubMed1999

MMPI variables predictive of schizophrenia in the Copenhagen High-Risk Project: a 25-year follow-up.

Moldin et al. (1) have identified a cluster of Minnesota Multiphasic Personality Inventory (MMPI) scales that discriminate adolescents at risk for schizophrenia from those not at risk. The present study examines how well Moldin's scales predict schizophrenic decompensation in a sample of 207 Danish adolescents at high genetic risk for schizophrenia. Subjects were assessed using a modified, 304-item MMPI in 1962 (mean age= 15.1 years) and diagnosed in 10-year and 25-year follow-ups. Premorbidly, schizophrenic subjects (n=31) scored higher than subjects with no mental illness on the frequency (F) and psychoticism (PSY) scales. When paranoid and non-paranoid preschizophrenics were separated, three scales (F, Pz (paranoid schizophrenia) and PSY) significantly discriminated paranoid preschizophrenics. Discriminant function analyses confirmed these results. It is concluded that the MMPI may be useful for identifying schizophrenia premorbidly.

Adolescent↗

PubMed1998

Leukocyte differentials predict short-term clinical outcome following antipsychotic treatment in schizophrenia.

BACKGROUND: The majority of patients with schizophrenia and many of their unaffected siblings exhibit a relative granulocytosis and lymphopenia. To characterize these abnormalities better, we examined leukocyte differentials and organ nonspecific autoantibodies in relationship to intake phenomenology and short-term clinical outcome. METHODS: We studied patients with schizophrenia (n = 81) and their siblings (n = 18). At intake assessment, about one-half of the probands (n = 38) were neurolepticnaive first-episode patients; the remainder were medication-free for at least 2 weeks. Hematologic indices were obtained at intake assessment, and psychiatric symptomatology was assessed at baseline and following 6 months of clinically determined treatment. RESULTS: A relative granulocytosis and lymphopenia prospectively predicted poorer recovery in positive, but not negative, symptoms after 6 months of antipsychotic treatment. Abnormal leukocyte proportions were specific to patients who presented with clinically significant positive symptomatology at intake. In contrast, clinically significant negative symptoms were only evident in a small subgroup of patients who were positive for antinuclear autoantibodies and/or rheumatoid factor. CONCLUSIONS: Future research should further test the hypothesis that a relative granulocytosis and lymphopenia reflect genetic loading for the pathophysiologic determinants of positive symptoms. Future research also should determine the etiologic significance of organ nonspecific autoimmunity in predominantly negative symptom schizophrenia.

Adult↗

PubMed1998

The genetic epidemiology of schizophrenia in a Finnish twin cohort. A population-based modeling study.

BACKGROUND: The magnitude of heritability of schizophrenia remains controversial, due in part to limitations of estimates derived from index twin pairs exclusively. We applied structural equation modeling in a total population of twins to determine the significance and magnitudes of the genetic and environmental contributions to schizophrenia. METHODS: All monozygotic (1180 male and 1315 female pairs) and same-sex dizygotic (2765 male and 2613 female pairs) twins born from 1940 to 1957 in Finland were screened for nonorganic psychotic disorder diagnoses as recorded on an inpatient or outpatient basis or from an eligibility review for a disability pension. RESULTS: The lifetime prevalence of schizophrenia was 2.0%, with a marginally higher prevalence in men (2.2%) than women (1.8%). Model fitting indicated that 83% of the variance in liability was due to additive genetic factors, and the remaining 17% was due to unique environmental factors. Sex-limitation modeling revealed no evidence of sex-specific genetic effects and no sex difference in the magnitude of heritability. A multiple threshold model incorporating affective and other psychoses as a phenotype intermediate between schizophrenia and no diagnosis was rejected. CONCLUSIONS: In a population-based twin study of schizophrenia, heritability was estimated at 83%, with the remaining variance in liability attributed to environmental factors not shared in common among co-twins. Despite the notable limitation of using diagnoses ascertained through treatment contacts, the heritability estimate in this study is almost identical to those reported in recent studies of index pairs using standardized applications of DSM-III or later criteria.

Adult↗

PubMed1998

Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls.

BACKGROUND: Cortical gray matter volume reductions and cerebrospinal fluid (CSF) volume increases are robust correlates of schizophrenia, but their sources have not been established conclusively. METHODS: Structured diagnostic interviews and magnetic resonance imaging scans of the brain were obtained on 75 psychotic probands (63 with schizophrenia and 12 with schizoaffective disorder), ascertained so as to be representative of all such probands in a Helsinki, Finland, birth cohort; 60 of their nonpsychotic full siblings; and 56 demographically similar control subjects without a personal or family history of treated psychiatric morbidity. RESULTS: Patients with schizophrenia and their siblings exhibited significant reductions in cortical gray matter volume and significant increases in sulcal CSF volume compared with controls. The patients, but not their siblings, also exhibited significant reductions in white matter volume and significant increases in ventricular CSF volume. Regional effects were most robust when component volumes were expressed as percentages of overall regional volumes; in this case, for patient and sibling groups, gray matter volume reductions and sulcal CSF volume increases were significantly more pronounced in the frontal and temporal lobes than in the remainder of the brain. None of the group differences varied significantly by sex or hemisphere. CONCLUSIONS: Structural alterations of the cerebral cortex, particularly in the frontal and temporal lobes, are present in patients with schizophrenia and in some of their siblings without schizophrenia; such changes are thus likely to reflect genetic (or shared environmental) effects. Ventricular enlargement is unique to the clinical phenotype and is thus likely to be affected primarily by nonshared causative factors.

Adult↗

PubMed1997

Structural brain abnormalities in schizophrenia: a family study.

Structural brain abnormalities such as ventricular enlargement are robust correlates of schizophrenia, but the degree of difference compared with unrelated normal controls is only moderate (< 1 standard deviation), and only 40% of patients have values on these measures that fall outside of the normal distribution. Family studies can help to clarify the meaning of this overlap by controlling for some of the non-schizophrenia-related genetic variation in neuroanatomical traits. Computerized tomographic scans of the brain were used to measure ventricular and sulcal cerebrospinal fluid (CSF) to brain ratios (VBR and SBR) for each hemisphere in 16 pairs of discordant siblings from the Copenhagen Schizophrenia High-Risk Project. Schizophrenics' values for VBR and SBR exceeded those of their nonschizophrenic siblings in 75% of the pairs; on average, patients' values on these measures were 1 and 5 standard deviations larger, respectively, than those of their nonschizophrenic siblings. Sulcal and left hemisphere effects were significantly more pronounced than ventricular and right hemisphere effects. After controlling for between-family variation, structural brain abnormalities appear to be more prevalent and more pronounced in schizophrenia than has previously been assumed, with relatively greater deviation observed for cortical and left hemisphere measures of CSF space enlargement.

Adult↗

PubMed1997

Attentional dysfunctions in neuroleptic-naive and neuroleptic-withdrawn schizophrenic patients and their siblings.

This study examined attentional deficits in 44 schizophrenic patients (24 neuroleptic-naive and 20 neuroleptic-withdrawn patients) across changes in medication status and clinical state using a 1-9 continuous performance test (CPT) with distractors. Patients' attentional selectivity scores (A') were unchanged from the off-medication to on-medication testings (on average, 6 months later), despite significant improvement in both positive and negative symptoms. Both patient groups had significantly lower A' scores than 44 matched healthy controls at each testing. The nonschizophrenic siblings (n = 15) of these patients made significantly more errors of omission and commission than healthy controls. The results suggest that attentional deficits, as measured by this CPT, appear to measure stable markers of schizophrenia that may be associated with genetic vulnerability to the illness.

Adolescent↗

PubMed1997

Childhood behavior precursors of schizotypal personality disorder.

No study has yet reported specifically on the early behavior of individuals later diagnosed with schizotypal personality disorder (SPD). This study examines prospectively collected teacher reports on school behavior as a means of assessing childhood precursors of SPD. Thirty-six DSM-III-R diagnosed schizotypal subjects were compared with four other groups: 31 schizophrenia patients, 37 diagnosed as nonpsychotic mentally ill, 68 who were not mentally ill but had mothers with schizophrenia, and 60 who were not mentally ill and had normal parents. These individuals were compared on a teachers' school report questionnaire obtained when the subjects averaged 15.1 years old. Those who later developed SPD were found to be more passive and unengaged and more hypersensitive to criticisms compared with the nonschizophrenia groups. Similar results were found when males and females were examined separately, except that males who developed SPD were found to be less disruptive and hyperexcitable compared with males with schizophrenia; females with SPD did not differ from females with schizophrenia. A receiver operating characteristic analysis found these factors to predict 73.5 percent of future SPDs; the ability of these factors to predict future SPDs is comparable for males and females. These findings suggest that preschizotypal traits may be identified in late childhood or adolescence.

Adolescent↗

PubMed1997

Effects of child-rearing by schizophrenic mothers: a 25-year follow-up.

We conducted a 25-year follow-up study of 50 children of schizophrenic mothers, consisting of 25 children reared by their mothers and 25 children reared apart. The children's adult psychiatric status was evaluated in a 3-h structured interview employing a battery of syndrome check-lists and scales. A slightly higher incidence of psychopathology (including schizophrenia-spectrum disorders) was found among the reared-apart subjects. This may possibly be attributed to their greater genetic predisposition, as suggested by their mothers' more severe illnesses. Lifetime diagnoses do not provide evidence that psychopathology in offspring at genetic risk is increased by rearing by a schizophrenic mother.

Adolescent↗

PubMed1996

Activation of the prefrontal cortex during judgments of recency: a functional MRI study.

Animal and human lesion studies have consistently shown that damage to the prefrontal lobe disrupts performance on tasks requiring memory for temporal context. In this study, functional magnetic resonance imaging (fMRI) was used to explore the brain regions associated with judgements of relative recency in healthy humans. Bilateral dorsolateral prefrontal cortex (Brodmann's area [BA] 9) was more active during a verbal recency judgment task than during a non-mnemonic control task. Activation related to temporal context recognition was also observed in midline supplementary motor area (BA 6) and left precuneus (BA 7). This study provides further evidence that memory for temporal context requires the prefrontal cortex and is the first to demonstrate this association in healthy humans. The current findings also suggest the possibility that recognition of context and recognition of episodic content may involve similar brain systems.

Adult↗

PubMed1996

Leukocytes and organ-nonspecific autoantibodies in schizophrenics and their siblings: markers of vulnerability or disease?

To determine whether leukocyte counts and organ-nonspecific autoantibodies mark familial vulnerability for schizophrenia and/or the disease itself, we examined 92 patients with schizophrenia and 94 unrelated, demographically balanced, healthy individuals. In addition, for 19 of the probands, one of their nonschizophrenia, full siblings also was recruited. At the time of the blood draw, most probands (87%) had been free of medications for a minimum of 2 weeks and about half were neuroleptic-naive, first-episode patients. Results indicate that a relative lymphopenia in the context of a relative granulocytosis appears to mark familial vulnerability for schizophrenia, whereas an absolute monocytosis appears to mark spectrum manifestations of the clinical phenotype. The former observation is consistent with the hypothesis that the etiology of schizophrenia is immunologically mediated, whereas the latter is consistent with emerging evidence that an inflammatory process is associated with the expression of the disorder. Neither antinuclear antibody nor rheumatoid factor emerged as liability or disease markers.

Adult↗

PubMed1996

Course of treatment response in first-episode and chronic schizophrenia.

OBJECTIVE: The timing and clinical correlates of symptom change following antipsychotic treatment were examined in first-episode and chronic schizophrenia. METHOD: The subjects were 36 first-episode schizophrenic patients who had received minimal or no neuroleptics and 34 patients with chronic illness whose neuroleptics had been withdrawn. They were followed for 2 years and assessed with the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. Treatment decisions during follow-up were made clinically by the treating physicians. RESULTS: At 6-month follow-up, both the neuroleptic-naive and previously treated patients showed significant improvement in positive symptoms (52% and 44% reductions from baseline, respectively). The previously treated but not the neuroleptic-naive patients also showed a significant reduction in negative symptoms (19% from baseline). A longer duration of illness before baseline assessment and inconsistent treatment during follow-up were independently associated with poorer treatment outcome in terms of positive symptoms in both groups. There were no significant changes on the outcome measures in either group after the 6-month follow-up. CONCLUSIONS: The results suggest that maximum symptomatic improvement occurs within the first 6 months of treatment and that disease progression may blunt treatment efficacy in both first-episode and chronic schizophrenia.

Adult↗

PubMed1996

Abnormalities of brain structure and function in schizophrenia: implications for aetiology and pathophysiology.

In vivo imaging and post-mortem neuropathology studies have detected a variety of abnormalities in brain function and structure in patients with schizophrenia. Current models of the neural mechanisms involved focus primarily on frontal and medial temporal lobe structures and their interconnections, because deficits in these systems are relatively prominent against a background of generalized cerebral dysfunction, and because individuals with acquired lesions in these areas show many of the symptoms characteristic of schizophrenia. Family and twin studies have demonstrated similar abnormalities in some of the unaffected biological relatives of schizophrenics, indicating that some of these neuropathological changes are mediated in part by genetic predisposition to the disorder. Further, obstetric complications are associated with an increased risk for phenotypic schizophrenia and with greater severity of its neuropathological features in individuals at elevated genetic risk. These latter findings, combined with evidence of heterotopic displacement of neurones in temporolimbic and frontal regions and evidence that cognitive dysfunction during childhood precedes schizophrenia, imply that at least some of these brain abnormalities are neuro-developmental in origin. The view emerging from this work is that schizophrenia is a brain disease the neuropathological features of which result at least in part from the unique and interacting influences of genetic factors and adverse obstetric events in utero.

Age of Onset↗

PubMed1995

The latent structure of schizotypy: I. Premorbid indicators of a taxon of individuals at risk for schizophrenia-spectrum disorders.

A taxometric analysis (R. R. Golden & P. E. Meehl, 1979) was conducted to test the hypotheses that liability for schizophrenia-spectrum disorders is dichotomously distributed and that this liability can be detected premorbidly with behavioral indicators analogous to many of the criteria for schizotypal personality disorder. Behaviors were assessed in 207 offspring of schizophrenic mothers and 104 matched offspring of normal parents in 1962, when participants' mean age was 15 years. Diagnoses on the basis of the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; American Psychiatric Association, 1987) were made in 1986-1989, when participants were nearly through the risk period for developing schizophrenia. The aggregation of indicators was consistent with a bimodal latent liability distribution. Membership in the schizotypal class was a sensitive and specific predictor of the emergence of schizophrenia-spectrum disorders in adulthood.

Adolescent↗

PubMed1994

Impaired autonomic nervous system-habituation in those at genetic risk for schizophrenia.

BACKGROUND: Schizophrenia has been associated with habituation of skin conductance activity. Skin conductance data from the Copenhagen High Risk Project were analyzed. We hypothesized that genetic risk for schizophrenia and development of schizophrenia later in life are related to impaired habituation of autonomic nervous system activity. METHODS: Data were collected in 1962, when subjects averaged 15 years of age and had not yet qualified for a psychiatric diagnosis. Nonspecific fluctuations in electrodermal activity were monitored during a rest period free of sensory stimulation. RESULTS: We found that an increasing level of genetic risk for schizophrenia was related to impaired habituation of autonomic nervous system activity over time. Individuals with two schizophrenia-spectrum parent evidenced no habituation, those with one spectrum parent evidence some habituation, and those with normal parents evidenced rapid habituation. Subjects who developed schizophrenia in adulthood evidenced significant deficits in habitation in adolescence. CONCLUSIONS: These results suggest that impaired habituation of spontaneous autonomic nervous system activity may represent a behavioral marker of the genetic predisposition to schizophrenia.

Adolescent↗

PubMed1994

Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers.

OBJECTIVE: To determine whether schizophrenics and their nonschizophrenic siblings have a similar pattern of neuropsychological deficit when compared with normal controls. DESIGN AND PARTICIPANTS: Fifteen probands with schizophrenia, 16 of their nonschizophrenic siblings, and 31 unrelated, demographically balanced, normal individuals underwent evaluation with a comprehensive neuropsychological test battery. All subjects were screened for history of head injury, neurologic illness, major medical conditions, substance use, and axis I psychiatric disorders other than schizophrenia. Probands underwent evaluation twice: once at intake when half had never received neuroleptic medication and the other half had received none for a minimum of 2 weeks, and again at the 2- to 4-week follow-up, after stabilization with neuroleptic medications. RESULTS: Both schizophrenics and their nonschizophrenic siblings were impaired neuropsychologically compared with normal controls, with the nonschizophrenic siblings' performance intermediate between that of the schizophrenic siblings and the normal controls on all measures of functioning. The shapes of the deficit profiles of schizophrenic patients and their siblings were similar; in patients, verbal memory, abstraction, attention, and language functions were significantly more affected compared with spatial abilities, spatial memory, and sensory-motor functions, with a nonsignificant trend in the same direction in siblings. Cognitive functioning in patients was found to be stable across changes in medication status and clinical state. Four fifths of patients obtained more deviant scores than their nonschizophrenic siblings. Among the sibling group, those with probable and certain diagnoses of schizotypal personality disorder were more impaired compared with those without schizophrenia-spectrum symptoms. CONCLUSION: These results support the hypothesis that impaired information processing aggregates in the family members of schizophrenics and may serve as an indicator of genetic vulnerability to the disorder. Further work is needed to establish whether particular areas of functioning are selectively impaired in relatives and to determine whether the performance deficits are mediated by structural and/or metabolic disturbances in specific brain regions.

Adult↗

PubMed1994

Developmental brain abnormalities in the offspring of schizophrenic mothers. II. Structural brain characteristics of schizophrenia and schizotypal personality disorder.

BACKGROUND: We examined differences in ventricular and sulcal cerebrospinal fluid-to-brain ratios as a function of lifetime psychiatric diagnosis in the offspring of schizophrenic mothers (high-risk sample) and in the offspring of normal parents (low-risk sample). METHODS: We used a cohort analytic study of 17 high-risk individuals with schizophrenia, 31 high-risk individuals with schizotypal personality disorder, 33 high-risk individuals with nonschizophrenia-spectrum psychiatric disorders, 45 high-risk individuals with no disorders, 31 low-risk individuals with psychiatric disorders of all types, and 46 low-risk individuals with no disorders, evaluated initially in 1962 when they were a mean age of 15 years, and reexamined from 1986 through 1989 with psychiatric interviews and computed tomographic scans of the brain. RESULTS: High-risk individuals with schizophrenia and schizotypal personality disorder evidenced an equivalent degree of cortical sulcal enlargement, and both groups evidenced significantly greater sulcal enlargement than did high-risk individuals with nonschizophrenia-spectrum disorders and no disorders and low-risk individuals with psychiatric disorders and no disorders. High-risk individuals with schizophrenia evidenced significantly greater ventricular enlargement than did high-risk and low-risk subjects with other disorders and no disorders, including those with schizotypal personality disorder. These differences were independent of age, gender, history of substance dependence, and history of organic brain syndromes and head injuries. CONCLUSIONS: Among the offspring of schizophrenic parents, cortical abnormalities are expressed equally across the range of syndromes in the schizophrenia spectrum. Subcortical abnormalities (ie, ventricular enlargement) are more pronounced in the more severe syndrome (ie, schizophrenia).

Adult↗