Disturbed frontal gyrification within families affected with schizophrenia.

OBJECTIVE: Recently, in a post-mortem and a subsequent structural MR study, a significantly increased gyrification index (GI) was demonstrated in the frontal lobe in individuals with schizophrenia. To examine whether frontal lobe hypergyria is region-specific and whether this might be a suitable endophenotype in the search for the genetic basis of schizophrenia, the frontal as well as parieto-occipital GI were determined in MRI scans of families affected with schizophrenia. METHOD: In the MRI scans of 48 subjects suffering from schizophrenia, in 82 of their first-degree relatives and in 41 control subjects, the GI was determined in three sections anterior to the genu of the corpus callosum and three sections posterior to the splenium, thus allowing for a selective determination of this measure in the frontal as well as the parietal lobe. Outer and inner contours constituting the GI was determined in each section by manual tracing. Statistical analysis was performed using MANOVA with factors diagnostic group and intervening factors from preliminary analyses. RESULTS: The frontal, but not parieto-occipital GI was significantly higher in schizophrenic patients as well as unaffected relatives compared with control subjects (right: 7%, F=13.24, df=3, 155, p<0.0005, left: 6%, F=8.92, df=3, 155, p<0.0005). There was no overall difference between affected and unaffected family members. On the left side however, there was a significant interaction between diagnostic group and genetic loading (F=4.68, df=2, 101, p=0.01): significantly higher GI was found in affected compared with unaffected family members only in uniaffected and not multiaffected families. CONCLUSIONS: These results support our primary finding of hypergyria in the frontal lobe in schizophrenic patients. Compared to the parietal lobe, hypergyria seems to affect the frontal lobe selectively and serves as a suitable neurodevelopmental, possibly even an endophenotypic marker.

Relation between cerebrospinal fluid, gray matter and white matter changes in families with schizophrenia.

BACKGROUND: Gray matter reduction and ventricular enlargement belong to the best replicated findings in schizophrenia. Brain morphologic changes were also found in non-schizophrenic family members (FM). The intention of this study was to examine whether non-psychotic first-degree relatives reveal similar morphologic changes as schizophrenic patients and how state of genetic loading contribute to these abnormalities. METHODS: Forty-nine schizophrenic patients, 71 non-schizophrenic FM and 48 control subjects took part in this volumetric MRI study. All subjects were between 18 and 59 years old. Dependent variables were gray matter, white matter and total cerebrospinal fluid (CSF) volume, determined by SPM99 segmentation algorithm. As an important part of CSF lateral ventricle volume was determined manually by removing surrounding CSF areas. RESULTS: In schizophrenic patients compared to controls and non-schizophrenic FM total CSF volumes and lateral ventricles were increased. Gray and, to a lesser degree, white matter volumes were decreased as well. For CSF, gray and white matter there was no significant difference between uni- and multiple affected families. CSF correlated significantly negative with gray matter (r=-0.78) and, less intensive, with white matter (r=-0.40). There were negative correlations between gray and white matter volume as well (r=-0.26). These correlations were not significantly different between the diagnostic groups. CONCLUSION: CSF enlargement and gray matter reductions in schizophrenic patients compared to controls and non-affected FM seem to be interdependent findings. However, this correlation is independent of the factor diagnosis and is therefore not specific for schizophrenia.

Reduction of the internal capsule in families affected with schizophrenia.

BACKGROUND: The anterior limb of the internal capsule (ALIC), connecting cortical and subcortical structures, is involved in functional important circuits. To detect volumetric changes in ALIC, including the influence of genetic factors, a magnetic resonance imaging (MRI) study of families affected with schizophrenia was performed. METHODS: The study sample comprised 22 family members with schizophrenia (FM-SZ), 34 family members without schizophrenia (FM-NSZ), and 43 control subjects. In addition to manual tracing of ALIC, subjects underwent proton magnetic resonance spectroscopy in the left prefrontal cortex, psychopathological rating, and neuropsychological assessment of frontal lobe function. RESULTS: Compared with controls, a significant reduction of right ALIC volume was seen in all family members (12%-16% reduction, p < .01) and a reduction of left ALIC volume in FM-NSZ (10% reduction, p = .028) was also observed. Both groups of family members showed a bilateral reduction in maximal cross sectional area of the ALIC. FM-SZ performed significantly worse on neurocognitive measures (Subject Ordered Pointing Task [SOPT] and Wisconsin Card Sorting Test), and performance correlated negatively with the ALIC volume (SOPT, r = -.6, p = .03). CONCLUSIONS: A reduced volume of ALIC in affected families supports the hypothesis of disturbed frontothalamic connectivity in schizophrenia and demonstrates functional relevance by an association with reduced neurocognitive performance.

[Volumetric analysis of gray matter, white matter and cerebrospinal fluid space in schizophrenia]. / Volumetrijska analiza sive mase, bele mase i prostora cerebrospinalne tecnosti u shizofreniji.

Schizophrenia is characterized by diffuse brain abnormalities, some of them involving volumes of three intracranial compartments: gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Novel methods, such as Statistical Parametrical Mapping, provide an automated means of comparing structural features across high quality MRI scans and the measurement based on the principles of voxel based morphometry. For the purposes of the present study, we selected sex balanced group of young adults with recent onset illness to assess the effects of the illness on the volumes of compartments and also to minimize the effects of chronicity, medication, sex and aging. Sixty-four subjects were selected from a larger sample (inclusion criteria: age range 18-31). Thirty-one had DSM IV diagnosis of schizophrenia or schizoaffective disorder, 33 were controls. T1 weighted MRI images were acquired on two scanners (1.5T both): a) fast gradient echo sequence, FLASH, 40 msec repetition time, 5 ms echo time, 40 degree flip angle and b) turbo gradient echo, 12 msec repetition time, 4 msec echo time, 20 degree flip angle, 1 excitation). The resulting data set consisted of: a) 128 consecutive slices with 1.17 mm thickness and 256 x 256 pixels per slice and b) 160 consecutive slices of 1 mm thickness and 256 x 256 pixels per slice. All 64 images were processed by ANALZYE, and normalized and segmented by SPM99. Following the automatic segmentation of the images into the three intracranial compartments, volumetry was performed based on the principles of voxel analysis. Results were expressed relative to whole brain volume, and MANOVA analyses were performed to correct the confounding effects of MRI acquisition center differences and age difference between diagnostic groups. Young adults with recent onset schizophrenia had 6% reduction in GM volume and 14% increase in the volume of CSF, after all confounders were included into analyses (MANCOVA: p = 0.006 and 0.0002, respectively). No significant changes in WM volume were evident. In comparison to a few similar studies published recently, all results yielded similar scores regarding effects of recent onset illness and young adult population, thus confirming the reliability of the procedure. In conclusion, global neuropil reduction was discussed as a consequence of the cortical neurodevelopmental disgenesis. It was suggested that neuropil reduction i.e. synaptic and dendritic changes were to induce functional abnormalities and the expression of schizophrenia.

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice.

The Cu-binding beta-amyloid precursor protein (APP), and the amyloid Abeta peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in Abeta levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS Abeta before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu.