Mean diffusivity: A biomarker for CSF-related disease and genetic liability effects in schizophrenia

Laboratory of Neuro Imaging, Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Psychiatry Research (Impact Factor: 2.47). 01/2009; 171(1):20-32. DOI: 10.1016/j.pscychresns.2008.03.008
Source: PubMed


Mean diffusivity (MD), the rotationally invariant magnitude of water diffusion that is greater in cerebrospinal fluid (CSF) and smaller in organized brain tissue, has been suggested to reflect schizophrenia-associated cortical atrophy. Regional changes, associations with CSF, and the effects of genetic predisposition towards schizophrenia, however, remain uncertain. Six-direction diffusion tensor imaging DTI and high-resolution structural images were obtained from 26 schizophrenia patients, 36 unaffected first-degree patient relatives, 20 control subjects and 32 control relatives (N=114). Registration procedures aligned diffusion tensor imaging (DTI) data across imaging modalities. MD was averaged within lobar regions and the cingulate and superior temporal gyri. CSF volume and MD were highly correlated. Significant bilateral temporal, and superior temporal MD increases were observed in schizophrenia compared with unrelated control probands. First-degree relatives of schizophrenia probands showed larger MD measures compared with controls within bilateral superior temporal regions with CSF volume correction. Superior temporal lobe brain tissue deficits and proximal CSF enlargements are widely documented in schizophrenia. Larger MD indices in patients and their relatives may thus reflect similar pathophysiological mechanisms. However, persistence of regional MD effects after controlling for CSF volume, suggests that MD is a sensitive biological marker of disease and genetic liability, characterizing at least partially distinct aspects of brain structural integrity.

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Available from: Robert F Asarnow
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    • "The number of DTI studies examining individuals at higher than average genetic risk for psychotic disorder is scant and sample sizes are, in general, small (number of high-risk individuals ranging from n = 16 to n = 34), except for one study (Boos et al., 2012). The available evidence suggests that white matter alterations may be present in first-degree relatives without symptoms (Munoz Maniega et al., 2008; Camchong et al., 2009; Hao et al., 2009; Narr et al., 2009; Clark et al., 2011; Boos et al., 2012; Knochel et al., 2012). The results for so-called " ultra-high risk " samples with (pre)clinical symptoms are conflicting (Peters et al., 2010), which likely is related to lack of consistency in ultra-high risk sample enrichment procedures across studies (van Os and Linscott, 2012) as well as to differences in brain regions studied and methodological approaches, precluding definite conclusions. "
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    ABSTRACT: Background: There is evidence for microstructural white matter alterations in patients with psychotic disorder, suggesting altered interregional connectivity. Less is known about the presence and role of white matter alterations in well individuals at higher than average genetic risk for psychotic disorder. Methods: 85 patients with psychotic disorder, 93 non-psychotic siblings of patients with psychotic disorder and 80 healthy controls underwent a diffusion tensor imaging (DTI) scanning protocol. In a whole brain voxel-based analysis using Tract Based Spatial Statistics (TBSS), fractional anisotropy (FA) values were compared between the three groups. Effects of antipsychotic medication and drug use were examined. Results: The patients displayed significantly lower mean FA than the controls in the following regions: corpus callosum (genu, body, splenium), forceps major and minor, external capsule bilaterally, corona radiata (anterior, posterior) bilaterally, left superior corona radiata and posterior thalamic radiation bilaterally. Similar FA differences existed between the patients and siblings; the siblings did not differ from the controls. Conclusion: Profound microstructural white matter alterations were found in the corpus callosum and other tracti and fasciculi in the patients with psychotic disorder, but not in siblings and the controls. These alterations may reflect brain pathology associated with the illness, illness-related environmental risk factors, or its treatment, rather than genetic risk.
    Full-text · Article · Mar 2013 · Schizophrenia Research
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    • "The current study provides new insights into the quantitative associations between aberrant WM fiber integrity and symptom severity across clinically healthy subjects with a genetic risk for SZ and patients with clinically manifest schizophrenia. Furthermore, our results support anatomical connectivity as a potential endophenotype of schizophrenia, which may be useful as a candidate biomarker to assess disease risk and to support early detection (Camchong et al., 2009; Hao et al., 2009; Narr et al., 2009; Bertisch et al., 2010; Knöchel et al., 2011). However, longitudinal studies and genetic association studies are necessary to confirm a potential predictive and diagnostic value of DTI in preclinical and clinical SZ. "
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    ABSTRACT: In this study, we investigate whether aberrant integrity of white matter (WM) fiber tracts represents a genetically determined biological marker of schizophrenia (SZ), and its relation with clinical symptoms. We collected brain DTI data from 28 SZ patients, 18 first-degree relatives and 22 matched controls and used voxel-based analysis with tract-based spatial statistics (TBSS) in order to compare fractional anisotropy (FA) between groups. Mean voxel-based FA values from the entire skeleton of each group were compared. We did a multiple regression analysis, followed by single post-hoc contrasts between groups. FA values were extracted from the statistically significant areas. The results showed significantly smaller FA values for SZ patients in comparison with controls in cortico-spinal tracts, in commissural fibers, in thalamic projections, in association fibers and in cingulum bundles. A significant increase of FA in SZ patients in comparison with healthy controls was only found in the arcuate fasciculus. Relatives had intermediate values between patients and controls which were deemed significant in the comparison to patients and controls in association fibers, arcuate fasciculus and cingulum bundles. Lower FA values in association fibers were significantly associated with predisposition toward hallucinations (in SZ patients and relatives), with higher PANSS scores of positive symptoms and with duration of illness (SZ patients). Our results suggest that clinical and subclinical presentations of psychotic symptoms are associated with aberrant integrity of multiple WM tracts. This association may represent an endophenotype of schizophrenia, since it is present in unaffected relatives as well. Such endophenotypes may serve as quantitative traits for future genetic studies and as candidate markers for early and preclinical identification of subjects at risk.
    Full-text · Article · Jul 2012 · Schizophrenia Research
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    • "MD of the diffusion tensor reflects the magnitude of water molecule movement that is independent of direction and contrasts with FA that assesses the directional preference of such movement (Le Bihan et al., 2001). Increased MD has been reported for instance in vascular and neurodegenerative disorders affecting the brain (Herve et al., 2005; Scola et al., 2010), schizophrenia (Lee et al., 2009; Narr et al., 2009) and autism (Lee et al., 2007) indicating less restricted and thus, increased movement of water molecules . Similarly in our present study, increased diffusion of water molecules in the frontal lobe of those with ASPD suggests a less coherent underlying WM microstructure. "
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    ABSTRACT: Antisocial personality disorder (ASPD) and psychopathy involve significant interpersonal and behavioural impairments. However, little is known about their underlying neurobiology and in particular, abnormalities in white matter (WM) microstructure. A preliminary diffusion tensor magnetic resonance imaging (DT-MRI) study of adult psychopaths employing tractography revealed abnormalities in the right uncinate fasciculus (UF) (Craig et al., 2009), indicating fronto-limbic disconnectivity. However, it is not clear whether WM abnormalities are restricted to this tract or are or more widespread, including other tracts which are involved in connectivity with the frontal lobe. We performed whole brain voxel-based analyses on WM fractional anisotropy (FA) and mean diffusivity (MD) maps acquired with DT-MRI to compare 15 adults with ASPD and healthy age, handedness and IQ-matched controls. Also, within ASPD subjects we related differences in FA and MD to measures of psychopathy. Significant WM FA reduction and MD increases were found respectively in ASPD subjects relative to controls. FA was bilaterally reduced in the genu of corpus callosum while in the right frontal lobe FA reduction was found in the UF, inferior fronto-occipital fasciculus (IFOF), anterior corona radiata and anterior limb and genu of the internal capsule. These differences negatively correlated with measures of psychopathy. Also in the right frontal lobe, increased MD was found in the IFOF and UF, and the corpus callosum and anterior corona radiata. There was a significant positive correlation between MD and psychopathy scores. CONCLUSIONS: The present study confirms a previous report of reduced FA in the UF. Additionally, we report for the first time, FA deficits in tracts involved in interhemispheric as well as frontal lobe connectivity in conjunction with MD increases in the frontal lobe. Hence, we provide evidence of significant WM microstructural abnormalities in frontal brain regions in ASPD and psychopathy.
    Full-text · Article · Jul 2011 · Cortex
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