David L. Garver

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bins average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

A genome scan meta-au2009nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142–168u2009Mb) and 2q (103–134u2009Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119–152u2009Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16–33u2009Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Cerebral Cortical Gray Expansion Associated with Two Second-Generation Antipsychotics

BACKGROUNDnSecond-generation antipsychotics (SGAs) differ from first-generation antipsychotics (FGAs) with respect to induction of less extrapyramidal morbidity, partially reducing negative symptoms, and causing modest improvement in neurocognitive functioning in patients with schizophrenia. SGAs demonstrate 5-HT2a antagonism. Differential effects of SGAs and FGAs on cortical gray volumes are explored herein.nnnMETHODSnCerebral cortical gray was examined volumetrically in 19 patients with schizophrenia before and following 28 days of treatment with two SGAs (risperidone and ziprasidone; n = 13) or a FGA (haloperidol; n = 6). Seven (untreated) control subjects were also assessed at a similar interval.nnnRESULTSnDuring treatment with the SGAs risperidone and ziprasidone, cerebral cortical gray of 13 patients with schizophrenia expanded 20.6 +/- 11.4 cc (p < .0005). Six patients receiving the FGA haloperidol, as well as 7 control subjects, showed no change in cortical gray volumes (p = .983 and p = .932, respectively) at the time of reassessment.nnnCONCLUSIONSnVolumetric increase of cerebral cortical gray occurred early in the course of treatment with the SGAs ziprasidone and risperidone, but not with the FGA haloperidol. Such cortical gray expansion may be relevant to the reported enhanced neurocognition and quality of life associated with SGA treatment.

Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia

Functional connection among the information-processing (grey-matter) centres within the CNS are necessary for the coordinated processing of perception, affect, thought and behaviour. Myelinated neuronal bundles provide the links among such processing centres. Magnetic resonance diffusion tensor imaging (DTI) can assess the physical integrity of myelin. Using DTI, the authors assessed diffusivity (Dm) within whole brain in 14 controls and within 13 acutely psychotic, drug-free schizophrenics both before and after 28 d of antipsychotic drug treatment. Drug-responder schizophrenicss (D-RS) (n=8) were differentiated from poor responders (PR) (n=5) according to previously defined criteria. Differences of Dm at both baseline and following treatment were assessed using Dm distributional analyses and Statistical Parametric Software (SPM2). Impaired physical integrity of myelin, demonstrated by an increase (overall p<0.05) of Dm, was found in the D-RS patients, with multiple regions demonstrating p<0.0005 patient-control differences. The pathological increase in Dm was reduced (p<0.03) following treatment-associated reduction of psychotic symptoms by 84%. Dm of PR patients did not differ from controls at baseline or following subacute treatment. While the pathophysiology(ies) underlying psychosis in poorly responsive (PR) schizophrenics does not appear to be related to a disordered myelin, the findings are consistent with a partially reversible disorder of myelin integrity, and may underlie a dys-synchrony of information processing in a major subgroup of drug-responsive patients with schizophrenia. An antipsychotic drug-induced cascade may partially restore myelin integrity and functional connectivity concomitant with antipsychotic effects in such D-RS patients.

Brain and ventricle instability during psychotic episodes of the schizophrenias.

Recent reports from serial brain scans suggest that the rate of ventricular expansion and/or brain atrophy may be accelerated in at least some schizophrenics. The authors assessed the effect of state changes upon such findings.Within-subject 3D MRIs were assessed for ventricular and brain volumes during periods of [partial] remission and of exacerbation of psychosis. Additional scans at comparable within-subject SAPS were used to assess rates of change in volumes that were independent of SAPS changes. Correlations of changes of ventricle and brain volumes vs. change of SAPS cores between scans revealed that ventricle volumes decreased during a period of psychotic exacerbation and increased at a time of [partial] remission (r(p)=-0.666; P<0.0005); conversely, brain volumes increased during psychotic exacerbation and decreased at [partial] remission (r(p)=+0.448; P=0.032). Scans at comparable SAPS scores suggested that the majority of patients had rates of ventricular expansion comparable to controls (0.9+/-0.6 cc/year), though two patients appeared to have rates of ventricular increase of 4.5+/-2. 1 cc/year (Lilliefores P=0.036; K-means clustering F=17.75). Exacerbation of psychosis in schizophrenia is accompanied by evidence of brain swelling, especially of periventricular brain, with encroachment of brain substance upon ventricular volumes. Controlled for state changes, the majority of schizophrenics show rates of ventricular expansion or brain atrophy indistinguishable from controls.

Schizophrenia spectrum disorders: an autosomal-wide scan in multiplex pedigrees.

Genome-wide linkage studies, examining the relationship between the schizophrenia syndrome(s) and possible susceptibility regions within the human genome have identified multiple regions within which linkage to the syndrome may be explored. No regions have been found to provide supportive evidence for linkage in all cohorts. These findings are consistent with the schizophrenia syndrome being genetically heterogeneous, with genetic susceptibility arising from multiple sites which are differentially distributed in from pedigree to pedigree. The authors present data from an autosomal-wide scan of 30 multiplex pedigrees, each with a mean of 4.1 members affected with a schizophrenia spectrum disorder with respect to regions of interest for linkage with the schizophrenia spectrum disease(s). Partial, though not significant replications of susceptibility sites at D1S518 (P=0.029) described by Shaw et al. (1998: Shaw, S.H., Kelly, M., Smith, A.B., Shields, G., Hopkins, P.J., Loftus, J., Laval, S.H., Vita, A., DeHert, M., Cardon, L.R., Crow, T.J., Sherrington, R., DeLisi, L.E., 1998. A Genome-wide search for schizophrenia susceptibility genes. Am. J. Med. Genet. (Neuropsychiatric Genet.) 81, 364-376.), and at D5S426 (P=0.015) described by : Silverman, J.M., Greenberg, D.A., Altstiel, L.D., Siever, L.J., Mohs, R.C., Smith, C.J., Zhou, G., Hollander, T.Y., Yang, X.-P., Kedache, M., Li, G., Zaccario, M.L., Davis, K.L., 1996. Evidence of a locus for schizophrenia and related disorders on the short arm of chromosome 5 in a large pedigree. Am. J. Med. Genet. 67, 162-171.) were documented using multipoint non-parametric (NPL) statistics. Two additional novel regions worthy of further investigation were identified at D1S1150 (P=0.004) and at D20S171 (P=0.009). Previously reported genomic regions of interest for the schizophrenias are reviewed in the context of the same/flanking markers utilized with the present cohort of pedigrees. The data further suggests that only a fraction of pedigrees multiplex for schizophrenia link at any single susceptibility region.

Volume increases in striatum associated with positive symptom reduction in schizophrenia: A preliminary observation

Eleven drug-free patients with a DSM-IV diagnosis of schizophrenia who were in a period of psychotic exacerbation were treated with antipsychotics for 4 weeks. To evaluate treatment-associated changes in the basal ganglia and in psychotic symptomatology, the patients were studied with magnetic resonance imaging and with the Scale for the Assessment of Positive Symptoms. Serial assessments of striatal volumes and psychotic symptoms were performed at baseline and at 4 weeks of treatment; dual assessments of striatal volumes were also performed in 11 untreated normal controls. Patients and controls did not differ in striatal volumes at baseline, but the patients demonstrated a significant posttreatment increase in striatal tissues (caudate-putamen). An increase in left striatum was not associated with drug treatment itself, but with a reduction of positive symptoms.

Thiobarbituric acid reactive substances in the cerebrospinal fluid in schizophrenia

Increased levels of lipid peroxidation products (thiobarbituric acid reactive substances [TBARS]) are reported in plasma/serum from patients with schizophrenia. CSF TBARS levels were assessed in 10 neuroleptic-free patients with schizophrenia and in 9 normal controls. Controlling for duration of storage, CSF TBARS content was significantly lower in patients with schizophrenia vs. controls (p<0.002). No significant correlations were found between CSF TBARS and patients age, gender, or duration of illness. The likely source of reported elevated plasma/serum TBARS in schizophrenia is therefore in the periphery. Degeneration of central neuronal membranes in schizophrenia is not supported by the present study.

State-related thalamic changes during antipsychotic treatment in schizophrenia: preliminary observations

Thalamic volumes and psychotic symptoms were assessed during psychotic exacerbation and during antipsychotic drug treatment. Reduction of psychotic symptoms (SAPS) during four weeks of treatment was highly correlated with volumetric expansion as measured by magnetic resonance imaging in both left and right thalamus [r(s)=0.75 and r(s)=0.82, respectively (both P<0.04)].

Magnetic resonance imaging study of brain asymmetries in dyslexic patients.

Research studies suggest that the left hemisphere is involved in the pathophysiology of dyslexia. Thus far, the exact location and nature of the purported lesion(s) remain a matter of contention. The present study describes the distribution of structural abnormalities as related to brain symmetry in the brains of dyslexic individuals. High-resolution three-dimensional magnetic resonance images (MRIs) were analyzed in 16 dyslexic men and 14 controls matched for sex, age, educational level, and handedness. A computerized image analysis system was used to assess the volumetric deformations required to match each brain with its left-right mirror image. The results showed significant abnormalities in five left hemisphere structures involving the extrapyramidal and limbic systems: amygdala, hippocampus proper, parahippocampal gyrus, putamen, and globus pallidus. The left hemisphere is thought to play a major role in the temporal analysis of information. This stream of temporal analysis is of importance in motor movements. Reading might have evolved as an exaptation to motor movements requiring the sequential analysis of information. (J Child Neurol 2005;20:842—847).