Chromosome Workshops 1998: current state of psychiatric linkage.
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Chromosomes, Human↗
Biomedical subjects
L E DeLisi
Publications and source records attributed to L E DeLisi.
Structural brain changes in schizophrenia.
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Brain↗
A new classification for the psychoses?
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Bipolar Disorder↗
Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia.
OBJECTIVE: The primary purpose of this article was to determine if cognitive abilities decline, remain unchanged, or modestly improve throughout the course of schizophrenic illness. METHOD: Forty-two patients with a first hospitalization for schizophrenia or schizophreniform disorder and 16 normal comparison subjects had a battery of neuropsychological tests and a magnetic resonance imaging (MRI) brain scan at approximate yearly intervals for the first 2 to 5 years of illness. Summary rating scales for language, executive, memory, processing speed, and sensory-perceptual functions were constructed. RESULTS: Patients with schizophrenia scored 1 to 2 standard deviations below normal comparison subjects on neuropsychological test measures during the course of the study. Patients exhibited less improvement than comparison subjects on measures of verbal memory. In general, improvement in positive symptoms over the time interval was associated with improvement in cognition. No changes in regional brain measurements were correlated with cognitive change in the patient group. CONCLUSIONS: Patients with schizophrenia have considerable cognitive dysfunction in the first 4 to 5 years of illness, which is stable at a level of 1 to 2 standard deviations below that of comparison subjects. There is little evidence for deterioration of cognitive abilities over the first few years of illness, with the exception of verbal memory, which shows significantly less improvement in patients over time relative to that of comparison subjects.
Adult↗
Reduction of the parahippocampal gyrus and the hippocampus in patients with chronic schizophrenia.
BACKGROUND: There have been many studies reporting reduced volume of the hippocampus or other limbic structures in patients with schizophrenia, but the literature is inconsistent. AIMS: To compare patients with either first-episode or chronic schizophrenia with controls using high-resolution volumetric magnetic resonance imaging (MRI) scans. METHOD: Thirteen patients with first-episode schizophrenia, 27 with chronic schizophrenia and 31 controls had 1.5 mm coronal slices taken through the whole brain using a spoiled-grass MRI acquisition protocol. RESULTS: The parahippocampal gyrus was reduced significantly on the left side in patients with chronic schizophrenia compared with controls for both male and female patients, whereas the hippocampus was reduced significantly on both sides only in female patients. There were no significant reductions in any structure between patients with first-episode schizophrenia and controls. CONCLUSIONS: Volumetric reduction seen in patients with chronic schizophrenia may be due to an active degenerative process occurring after the onset of illness.
Adult↗
Association of brain structural change with the heterogeneous course of schizophrenia from early childhood through five years subsequent to a first hospitalization.
Fifty first-episode patients with schizophrenia were followed for 5 years subsequent to their first hospitalization. The course of illness was charted prospectively and premorbid childhood histories were obtained retrospectively at the initial evaluation, and MRI scans were obtained initially and at each follow-up. Fifteen different life-time patterns of illness course emerged, although none were specifically associated with structural brain change. A deterioration in premorbid scores was positively correlated with larger ventricular volume at the first hospitalization, and the larger the ventricles, the less the subsequent change in ventricular size thereafter. An analysis to see whether initial hemispheric and ventricular size could predict different course types only revealed that patients with an acute onset and complete recovery had significantly smaller ventricles than all others. No differences emerged for initial hemispheric size. Thirty-four percent of patients individually showed some association of brain ventricular size and 28% hemisphere volume reductions with fluctuation in psychotic symptoms. Paradoxically, most showed larger ventricles and smaller hemispheres to be associated with clinical improvement, rather than the predicted reverse. These latter data question the notion that the structural brain changes seen over time in some patients are related to poor outcome, although small ventricular size in those patients with acute onset may be predictive of recovery. Thus, brain structural change is occurring early in the course of illness and may be a consequence of the process leading to resolution.
Adolescent↗
A genome-wide search for schizophrenia susceptibility genes.
We completed a systematic genome-wide search for evidence of loci linked to schizophrenia using a collection of 70 pedigrees containing multiple affected individuals according to three phenotype classifications: schizophrenia only (48 pedigrees; 70 sib-pairs); schizophrenia plus schizoaffective disorder (70 pedigrees; 101 sib-pairs); and a broad category consisting of schizophrenia, schizoaffective disorder, paranoid or schizotypal personality disorder, psychosis not otherwise specified (NOS), delusional disorder, and brief reactive psychosis (70 pedigrees; 111 sib-pairs). All 70 families contained at least one individual affected with chronic schizophrenia according to DSM-III-R criteria. Three hundred and thirty-eight markers spanning the genome were typed in all pedigrees for an average resolution of 10.5 cM (range, 0-31 cM) and an average heterozygosity of 74.3% per marker. The data were analyzed using multipoint nonparametric allele-sharing and traditional two-point lod score analyses using dominant and recessive, affecteds-only models. Twelve chromosomes (1, 2, 4, 5, 8, 10, 11, 12, 13, 14, 16, and 22) had at least one region with a nominal P value <0.05, and two of these chromosomes had a nominal P value <0.01 (chromosomes 13 and 16), using allele-sharing tests in GENEHUNTER. Five chromosomes (1, 2, 4, 11, and 13) had at least one marker with a lod score >2.0, allowing for heterogeneity. These regions will be saturated with additional markers and investigated in a new, larger set of families to test for replication.
Chromosome Mapping↗
Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosome.
The hypothesis that psychosis arises as a part of the genetic diversity associated with the evolution of language generates the prediction that illness will be linked to a gene determining cerebral asymmetry, which, from the evidence of sex chromosome aneuploidies, is present in homologous form on the X and Y chromosomes. We investigated evidence of linkage to markers on the X chromosome in 1) 178 families multiply affected with schizophrenia or schizoaffective disorder with a series of 16 markers spanning the centromere (study 1), and 2) 180 pairs of left-handed brothers with 14 markers spanning the whole chromosome (study 2). In study 1, excess allele-sharing was observed in brother-brother pairs (but not brother-sister or a small sample of sister-sister pairs) over a region of approximately 20 cM, with a maximum LOD score of 1.5 at DXS991. In study 2, an association between allele-sharing and degree of left-handedness was observed extending over approximately 60 cM, with a maximum lod score of 2.8 at DXS990 (approximately 20 cM from DXS991). Within the overlap of allele-sharing is located a block in Xq21 that transposed to the Y chromosome in recent hominid evolution and is now represented as two segments on Yp. In one of two XX males with psychosis we found that the breakpoint on the Y is located within the distal region of homology to the block in Xq21. These findings are consistent with the hypothesis that an X-Y homologous determinant of cerebral asymmetry carries the variation that contributes to the predisposition to psychotic illness.
Female↗
Familial associations of subsyndromes of psychosis in affected sibling pairs with schizophrenia and schizoaffective disorder.
Attempts to describe the clinical heterogeneity of schizophrenia have consisted of categorical subtyping and a dimensional approach using factor analysis. The latter has yielded three dimensions or subsyndromes: positive, negative and disorganisation. The aim of this study is to explore to what degree these subsyndromes are correlated within 114 sibling pairs (185 individuals) with DSM-III-R schizophrenia or schizo-affective disorder who were assessed for the lifetime presence or absence of the positive, negative, affective and disorganisation subsyndromes. Ratings were based on the core symptoms of each subsyndrome using a modified Krawieka scale. First rank symptoms were also included in the analysis. Coincidence was assessed by application of the binomial theorem to the frequency of occurrence of subsyndromes in this set of siblings. The disorganisation subsyndrome was shared above chance expectation (chi2=9.15, P < 0.01 for all sibling pairs). The significant results for the disorganisation subsyndrome suggest that it may be a suitable phenotypic marker for genetic linkage studies.
Adult↗
Sex differences in neuropsychological functioning of first-episode and chronically ill schizophrenic patients.
OBJECTIVE: The purpose of this study was to determine whether men and women with schizophrenia demonstrate differences in cognitive abilities. METHOD: Two cohorts of patients with schizophrenia, an acute first-episode and a chronically hospitalized group, were evaluated with a neuropsychological battery and compared with a normal group of subjects. RESULTS: After adjustment for age, age at onset, and premorbid IQ, male chronic patients performed worse than female chronic patients on measures of visual memory. These differences were eliminated after control for symptom severity. No other differences were found in cognitive function between men and women in either cohort. CONCLUSIONS: Sex differences in cognitive function in schizophrenic patients are not robust findings.
Age of Onset↗
The genetics of schizophrenia: past, present, and future concepts.
Although a genetic susceptibility for schizophrenia has been long established and even noted by Kraepelin in 1907, the mechanisms for its inheritance remains unknown. No candidates have proven to be correct and while many weakly positive chromosomal linkages have been reported, none have yet been consistently replicated. The following review examines the present status of these findings. The conclusion is that the field must move on to finding a consistently replicable mutation segregating with schizophrenia in families, before any of the present linkage results can be resolved.
Chromosome Mapping↗
Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia.
Brain structural deviation is known to be present in chronic patients with schizophrenia when compared with normal age-matched individuals. While the assumption is that these differences are based on a neurodevelopmental disturbance, whether they are static or continue to change throughout the disease process remains unknown. The following report describes a prospective follow-up study of first episode cases of schizophrenic illness. Analyses of MRI evaluations on an approximate annual basis for a minimum of four years are presented on 50 patients and 20 controls. Computer-assisted image analysis measuring the volume of several brain regions, using the program ANALYZE (Mayo Clinic), was performed on all scans. Patients were compared with controls for the rate of change over time in size of structures. No differences were found for the volumes of the caudate nucleus, temporal lobes, or hippocampus; and no changes in the degree of cerebral laterality were detected. However, there was a significant difference in the rate of change in the overall volumes of left and right hemispheres (P < 0.0004 and 0.001, respectively), right cerebellum (P < 0.02) and area of the isthmus of the corpus callosum (P < 0.05). The left cerebral ventricle had significantly greater enlargement over time when measured on coronal slice sequences (P < 0.02), but was not detected by axial views. These findings suggest that a subtle active brain process may be continuing through the first few years of a schizophrenic illness causing greater than the normal adult cortical deterioration. Further studies using other methods of image analysis and over a longer period of time are needed to determine the course and nature of this biologic process.
Adult↗
A linkage study of schizophrenia to markers within Xp11 near the MAOB gene.
A sex chromosome locus for psychosis has been considered on the basis of some sex differences in genetic risk and expression of illness, and an association with X-chromosome anomalies. Previous molecular genetic studies produced weak evidence for linkage of schizophrenia to the proximal short arm of the X-chromosome, while some other regions were not ruled out. Here we report an attempt to expand the Xp findings in: (i) a multicenter collaboration focusing on 92 families with a maternal pattern of inheritance (Study I), and (ii) an independent sample of 34 families unselected for parental mode of transmission (Study II). In the multicenter study, a parametric analysis resulted in positive lod scores (highest of 1.97 for dominant and 1.19 for recessive inheritance at a theta of 0.20) for locus DXS7, with scores below 0.50 for other markers in this region (MAOB, DXS228, and ARAF1). Significant allele sharing among affected sibling pairs was present at DXS7. In the second study, positive lod scores were observed at MAOB (highest of 2.16 at a theta of 0.05 for dominant and 1.64 at a theta of 0.00 for recessive models) and ALAS2 (the highest of 1.36 at a theta of 0.05 for a recessive model), with significant allele sharing (P = 0.003 and 0.01, respectively) at these two loci. These five markers are mapped within a small region of Xp11. Thus, although substantial regions of the X-chromosome have been investigated without evidence for linkage being found, a locus predisposing to schizophrenia in the proximal short arm of the X-chromosome is not excluded.
Chromosome Mapping↗
Language processing and memory in ill and well siblings from multiplex families affected with schizophrenia.
The present study was designed to extend the investigation of genetic factors for schizophrenia to cognitive and linguistic signs of central nervous system dysfunction. Of 51 siblings studied from 19 schizophrenia multiplex families, 37 had a DSM-III-R diagnosis of schizophrenia or related schzophrenia spectrum disorder and 14 were well. Controls were 17 unrelated healthy individuals within the same social class and age range. Subjects were tested on measures of memory, attention, reading and expressive language ability. Schizophrenic and spectrum disorder siblings were significantly more impaired in tests of auditory discrimination and memory than their well siblings or controls and displayed significantly reduced syntactic complexity to their speech. While well siblings did not differ from controls on most measures, some aspects of language complexity were reduced. A familial effect was observed for tests of reading ability, attention, some syntactic measures, and short-term memory, although these were not the measures that distinguished patients from controls in this cohort, the scores were not correlated among the ill sibling pairs, and poorer scores did not segregate with schizophrenia within these families. Thus, while some measures of language, memory and attention are deviant in patients with schizophrenia, they may not be heritable and directly related to the genetics of the disorder. Instead, they may be a manifestation of, rather than a vulnerability to, the illness.
Adult↗
Is schizophrenia a lifetime disorder of brain plasticity, growth and aging?
Chronic schizophrenia is characterized by change in the normal brain cortical structure, asymmetric reduction, and ventricular enlargement. The debate continues as to whether these anomalies occur early in development or represent an active progressive process continuing after the onset of psychosis. The case is made in the present manuscript for a continuing aberrant lifetime brain process. It is proposed that the underlying basis for the neuropathology of schizophrenia resides in the periodic activation of a defective gene or genes that determine the rate of cerebral growth. This process causes subtle cortical maldevelopment prenatally and through early childhood, is activated again during adolescent pruning of neurons, and again during the gradual aging process in the brain throughout adulthood. The case for a progressive active brain process in schizophrenia is thus presented.
Adolescent↗
Anomalous cerebral asymmetry and language processing in schizophrenia.
Reversal or reduction of normal structural cerebral asymmetries may be related to the pathogenesis of schizophrenia, but this relationship remains controversial. We review the literature and describe a further study designed to detect whether anomalous asymmetries are present early in the illness (at the first episode), whether they predict deficits in language processing, and whether they may be related to a genetic predisposition for schizophrenia. Asymmetries of brain widths and segments of the sylvian fissure were assessed in a magnetic resonance imaging study of 87 patients with a first episode of schizophrenia and 52 normal controls. These asymmetries were correlated with specific measures of language processing, memory, and hand skill. An independent group of 14 pairs of siblings with schizophrenia were also evaluated for evidence of heritability to cerebral asymmetries. Width asymmetries were reduced in patients compared with controls in the posterior (p = 0.02) and occipital (p = 0.05) regions. Brain horizontal length, on the other hand, was significantly more asymmetrical in patients (left > right; p = 0.04). For sylvian fissure measurements, asymmetries in controls (left > right) were greatest for the horizontal component; this asymmetry tended to detect differences in patients by comparison with controls (p < 0.06). In a range of tests of language and memory, few significant correlations between performance and cerebral asymmetries were detected either in patients or controls, although patients consistently scored poorer than controls in the majority of tests. In 14 pairs of psychotic siblings, within-pair correlations for the horizontal sylvian fissure asymmetry were significantly greater than between-pair correlations. These findings are consistent with the early presence (possibly genetic) of anomalous cerebral asymmetry. However, the functional correlates of reduced asymmetry remain obscure.
Adult↗
Gender and age at onset of schizophrenia.
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Age of Onset↗
Chromosome 18 translocation (18;21) (p11.1;p11.1) associated with psychosis in one family.
In the course of recruiting families with 2 schizophrenic siblings for genome screening and linkage studies, a family was found with mental retardation, schizophrenia, and/or other related psychotic illnesses in individuals who also had an unbalanced or balanced translocation between chromosomes 21-18 [t(18;21)(p11.1;p11.1)]. The pericentric region of chromosome 18 has already been noted as a possible location of a gene for bipolar psychosis. The family described here provides further evidence that this region should be examined for a candidate psychosis gene.
Adult↗