Publications by authors named "George Bartzokis"

71 Publications

Abnormal Trajectory of Intracortical Myelination in Schizophrenia Implicates White Matter in Disease Pathophysiology and the Therapeutic Mechanism of Action of Antipsychotics.

Biol Psychiatry Cogn Neurosci Neuroimaging 2018 05 14;3(5):454-462. Epub 2017 Mar 14.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

Background: Postmortem and imaging studies provide converging evidence that the frontal lobe myelination trajectory is dysregulated in schizophrenia (SZ) and suggest that early in treatment, antipsychotic medications increase intracortical myelin (ICM). We used magnetic resonance imaging to examine whether the ICM trajectory in SZ is dysregulated and altered by antipsychotic treatment.

Methods: We examined 93 subjects with SZ (64 men and 29 women) taking second-generation oral antipsychotics with medication exposures of 0-333 months in conjunction with 80 healthy control subjects (52 men and 28 women). Frontal lobe ICM volume was estimated using a novel dual contrast magnetic resonance imaging method that combines two images that track different tissue components.

Results: When plotted against oral antipsychotic exposure duration, ICM of subjects with SZ was higher as a function of medication exposure during the first year of treatment but declined thereafter. In the age range examined, ICM of subjects with SZ was lower with increased age, while ICM of healthy control subjects was not.

Conclusions: In adults with SZ, the relationship between length of exposure to oral second-generation antipsychotics and ICM was positive during the first year of treatment but was negative after this initial period, consistent with suboptimal later adherence after initial adherence. This ICM trajectory resembles clinically observed antipsychotic response trajectory with high rates of remission in the first year followed by progressively lower response rates. The results support postmortem evidence that SZ pathophysiology involves ICM deficits and suggest that correcting these deficits may be an important mechanism of action for antipsychotics.
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http://dx.doi.org/10.1016/j.bpsc.2017.03.007DOI Listing
May 2018

Altering the course of schizophrenia: progress and perspectives.

Nat Rev Drug Discov 2016 07 4;15(7):485-515. Epub 2016 Mar 4.

Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, Maryland MD21205, USA.

Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to - and of - this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.
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http://dx.doi.org/10.1038/nrd.2016.28DOI Listing
July 2016

Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.

Brain 2015 Jul 5;138(Pt 7):2087-102. Epub 2015 May 5.

1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.
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http://dx.doi.org/10.1093/brain/awv106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572484PMC
July 2015

Communication of brain network core connections altered in behavioral variant frontotemporal dementia but possibly preserved in early-onset Alzheimer's disease.

Proc SPIE Int Soc Opt Eng 2015 Mar;9413

Imaging Genetics Center, Institute for Neuroimaging & Informatics, University of Southern California, Los Angeles, CA, USA.

Diffusion imaging and brain connectivity analyses can assess white matter deterioration in the brain, revealing the underlying patterns of how brain structure declines. Fiber tractography methods can infer neural pathways and connectivity patterns, yielding sensitive mathematical metrics of network integrity. Here, we analyzed 1.5-Tesla whole-brain diffusion-weighted images from 64 participants - 15 patients with behavioral variant frontotemporal dementia (bvFTD), 19 with early-onset Alzheimer's disease (EOAD), and 30 healthy elderly controls. Using whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We evaluated the brain's networks focusing on the most highly central and connected regions, also known as , in each diagnostic group - specifically the "high-cost" structural backbone used in global and regional communication. The high-cost backbone of the brain, predicted by fiber density and minimally short pathways between brain regions, accounted for 81-92% of the overall brain communication metric in all diagnostic groups. Furthermore, we found that the set of pathways interconnecting high-cost and high-capacity regions of the brain's communication network are globally and regionally altered in bvFTD, compared to healthy participants; however, the overall organization of the high-cost and high-capacity networks were relatively preserved in EOAD participants, relative to controls. Disruption of the major central hubs that transfer information between brain regions may impair neural communication and functional integrity in characteristic ways typical of each subtype of dementia.
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http://dx.doi.org/10.1117/12.2082352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384394PMC
March 2015

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity.

Alzheimers Dement 2015 Feb 27;11(2):111-25. Epub 2014 Sep 27.

Kawamura Gakuen Woman's University, Abiko-city, Japan.

Background: An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.

Methods: Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T.

Results: The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001).

Conclusions: The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.
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http://dx.doi.org/10.1016/j.jalz.2014.05.1756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422168PMC
February 2015

Delphi definition of the EADC-ADNI Harmonized Protocol for hippocampal segmentation on magnetic resonance.

Alzheimers Dement 2015 Feb 15;11(2):126-38. Epub 2014 Aug 15.

LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine), IRCCS - S. Giovanni di Dio - Fatebenefratelli Brescia, Italy; Memory Clinic and LANVIE (Laboratory of Neuroimaging of Aging), University Hospitals and University of Geneva, Geneva, Switzerland.

Background: This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation.

Methods: The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests.

Results: Agreement was significant on the inclusion of alveus/fimbria (P = .021), whole hippocampal tail (P = .013), medial border of the body according to visible morphology (P = .0006), and on this combined set of features (P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer's disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates.

Discussion: Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.
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http://dx.doi.org/10.1016/j.jalz.2014.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419736PMC
February 2015

The early longitudinal course of cognitive deficits in schizophrenia.

J Clin Psychiatry 2014 ;75 Suppl 2:25-9

UCLA Semel Institute for Neuroscience and Human Behavior, 300 UCLA Medical Plaza, Room 2240, Los Angeles, CA 90095-6968

Cognitive impairment is a core feature of schizophrenia. However, the longitudinal course and pattern of this impairment, and its relationship to functional outcome, are not fully understood. Among the likely factors in the persistence of cognitive deficits in schizophrenia are brain tissue changes over time, which in turn appear to be related to antipsychotic medication adherence. Cognitive deficits are viewed as a core feature of schizophrenia primarily because cognitive deficits clearly exist before the onset of psychosis and can predict illness onset among those at high risk of developing the illness. Additionally, these deficits often persist during symptomatic remissions in patients and are relatively stable across time both in patients and in individuals at risk for schizophrenia. Despite clear evidence that cognitive impairment can predict functional outcome in chronic schizophrenia, results of studies examining this relationship in the early phase of psychosis have been mixed. Recent data, however, strongly suggest that interventions targeting early cognitive deficits may be crucial to the prevention of chronic disability and thus should be a prominent target for therapy. Finally, it is vital to keep schizophrenia patients consistently on their antipsychotic medications. A novel method of examining intracortical myelin volume indicated that the choice of antipsychotic treatment had a differential impact on frontal myelination. These data suggest that long-acting injectable antipsychotic medication may prevent patients from declining further through a combination of better adherence and pharmacokinetics.
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http://dx.doi.org/10.4088/JCP.13065.su1.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081490PMC
August 2014

Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees.

JAMA Psychiatry 2014 Apr;71(4):375-87

Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.

Importance: Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes.

Objective: To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk.

Design, Setting, And Participants: Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I.

Main Outcomes And Measures: Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes.

Results: Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture.

Conclusions And Relevance: To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.
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http://dx.doi.org/10.1001/jamapsychiatry.2013.4100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045237PMC
April 2014

Younger age of dementia diagnosis in a Hispanic population in southern California.

Int J Geriatr Psychiatry 2014 Jun 29;29(6):586-93. Epub 2014 Jan 29.

Easton Center for Alzheimer Disease Research, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Greater Los Angeles Veterans Affairs Healthcare System, Sepulveda Ambulatory Care Center, US Department of Veterans Affairs, Los Angeles, CA, USA; Department of Psychiatry Olive View, UCLA Medical Center, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, School of Medicine, UCLA, Los Angeles, CA, USA.

Objective: Prior studies of US Hispanics, largely performed on the East Coast, have found a younger age of dementia onset than in White non-Hispanics. We performed a cross-sectional study to examine clinical and sociodemographic variables associated with age of dementia diagnosis in older Hispanics and White, non-Hispanics in southern California.

Methods: Two hundred ninety (110 Hispanic and 180 White non-Hispanic) community dwelling, cognitively symptomatic subjects, aged 50 years and older, were assessed and diagnosed with probable Alzheimer's disease or probable vascular dementia. Apolipoprotein E (APOE) genotype was assessed in a subset of cases. Analysis of variance and multiple stepwise linear regression were used to assess main effects and interactions of ethnicity with dementia severity (indexed by mini mental state examination scores) and other sociodemographic and clinical variables on age of dementia diagnosis.

Results: Hispanics were younger by an average of 4 years at the time of diagnosis, regardless of dementia subtype, despite a similar prevalence of the APOE ε4 genotype. The earlier age at diagnosis for Hispanics was not explained by gender, dementia severity, years of education, history of hypercholesterolemia, hypertension, or diabetes. Only ethnicity was significantly associated with age of onset.

Conclusions: These findings confirm that US Hispanics living in the southwestern USA tend to be younger at the time of dementia diagnosis than their White non-Hispanic counterparts. As this is not explained by the presence of the APOE ε4 genotype, further studies should explore other cultural, medical, or genetic risk factors influencing the age of dementia onset in this population.
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http://dx.doi.org/10.1002/gps.4040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013239PMC
June 2014

Rich club network analysis shows distinct patterns of disruption in frontotemporal dementia and Alzheimer's disease.

Math Vis 2014;2014:13-22

Imaging Genetics Center, Institute for Neuroimaging & Informatics, University of Southern California, Los Angeles, CA, USA.

Diffusion imaging and brain connectivity analyses can reveal the underlying organizational patterns of the human brain, described as complex networks of densely interlinked regions. Here, we analyzed 1.5-Tesla whole-brain diffusion-weighted images from 64 participants - 15 patients with behavioral variant frontotemporal (bvFTD) dementia, 19 with early-onset Alzheimer's disease (EOAD), and 30 healthy elderly controls. Based on whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We examined how bvFTD and EOAD disrupt the weighted 'rich club' - a network property where high-degree network nodes are more interconnected than expected by chance. bvFTD disrupts both the nodal and global organization of the network in both low- and high-degree regions of the brain. EOAD targets the global connectivity of the brain, mainly affecting the fiber density of high-degree (highly connected) regions that form the rich club network. These rich club analyses suggest distinct patterns of disruptions among different forms of dementia.
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http://dx.doi.org/10.1007/978-3-319-11182-7_2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492471PMC
January 2014

Regional differences in white matter breakdown between frontotemporal dementia and early-onset Alzheimer's disease.

J Alzheimers Dis 2014 ;39(2):261-9

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Greater Los Angeles VA Healthcare System, West Los Angeles, CA, USA.

Background: White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).

Objective: Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting.

Methods: We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale for Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants.

Results: Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group.

Conclusions: The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.
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http://dx.doi.org/10.3233/JAD-131481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947877PMC
October 2014

Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer's disease detected in vivo with magnetic resonance imaging.

J Alzheimers Dis 2013 ;37(1):127-36

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Background: Iron can catalyze damaging free radical reactions. With age, iron accumulates in brain gray matter regions and may contribute to the risk of developing age-related diseases such as Alzheimer's disease (AD). Prior MRI studies demonstrated increased iron deposits in basal ganglia regions; however, the hippocampus (Hipp), which is heavily damaged in AD, and comparator regions that are resistant to AD damage, such as thalamus (Th), have rarely been examined.

Objective: To assess iron levels and evidence of tissue damage in Hipp and Th of AD subjects and healthy controls.

Methods: Thirty-one AD and sixty-eight healthy control subjects participated in this study. High- and low-field strength MRI instruments were used in combination to quantify iron content of ferritin molecules (ferritin iron) using the field dependent relaxation rate increase (FDRI) method. Decreased transverse relaxation rate (R2) was used as an index of tissue damage.

Results: Compared with healthy controls, AD subjects had increased ferritin iron in Hipp (p = 0.019) but not Th (p = 0.637), and significantly decreased R2 in Hipp (p < 0.001) but not Th (p = 0.37). In the entire sample, FDRI and R2 were negatively correlated.

Conclusion: The data shows that in AD, Hipp damage occurs in conjunction with ferritin iron accumulation. Prospective studies are needed to evaluate how increasing iron levels may influence the trajectory of tissue damage and cognitive and pathologic manifestations of AD.
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http://dx.doi.org/10.3233/JAD-130209DOI Listing
April 2014

Methodological improvements in voxel-based analysis of diffusion tensor images: applications to study the impact of apolipoprotein E on white matter integrity.

J Magn Reson Imaging 2014 Feb 15;39(2):387-97. Epub 2013 Apr 15.

Department of Physics, San Diego State University, San Diego, California, USA.

Purpose: To identify regional differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) using customized preprocessing before voxel-based analysis (VBA) in 14 normal subjects with the specific genes that decrease (apolipoprotein [APO] E ε2) and that increase (APOE ε4) the risk of Alzheimer's disease.

Materials And Methods: Diffusion tensor images (DTI) acquired at 1.5 Tesla were denoised with a total variation tensor regularization algorithm before affine and nonlinear registration to generate a common reference frame for the image volumes of all subjects. Anisotropic and isotropic smoothing with varying kernel sizes was applied to the aligned data before VBA to determine regional differences between cohorts segregated by allele status.

Results: VBA on the denoised tensor data identified regions of reduced FA in APOE ε4 compared with the APOE ε2 healthy older carriers. The most consistent results were obtained using the denoised tensor and anisotropic smoothing before statistical testing. In contrast, isotropic smoothing identified regional differences for small filter sizes alone, emphasizing that this method introduces bias in FA values for higher kernel sizes.

Conclusion: Voxel-based DTI analysis can be performed on low signal to noise ratio images to detect subtle regional differences in cohorts using the proposed preprocessing techniques.
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http://dx.doi.org/10.1002/jmri.24157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775904PMC
February 2014

Patterns of brain atrophy in clinical variants of frontotemporal lobar degeneration.

Dement Geriatr Cogn Disord 2013 9;35(1-2):34-50. Epub 2013 Jan 9.

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Background/aims: The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups.

Methods: Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects.

Results: Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology.

Conclusion: The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.
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http://dx.doi.org/10.1159/000345523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609420PMC
August 2013

Myelin breakdown mediates age-related slowing in cognitive processing speed in healthy elderly men.

Brain Cogn 2013 Feb 27;81(1):131-8. Epub 2012 Nov 27.

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States.

Background: To assess the hypothesis that in a sample of very healthy elderly men selected to minimize risk for Alzheimer's disease (AD) and cerebrovascular disease, myelin breakdown in late-myelinating regions mediates age-related slowing in cognitive processing speed (CPS).

Materials And Methods: The prefrontal lobe white matter and the genu of the corpus callosum myelinate later in brain development (late-myelinating white matter; LMWM) and are more vulnerable to breakdown due to the effects of normal aging. An in vivo MRI biomarker of myelin integrity (transverse relaxation rates; R(2)) of LMWM was obtained for 38 very healthy elderly adult men (mean age=66.3 years; SD=6.0; range=55-76). To evaluate regional specificity, we also assessed a contrasting early-myelinating region (splenium of the corpus callosum; SWM), which primarily contains axons involved in visual processing. CPS was assessed using the Trail Making Test.

Results: LMWM R(2) and CPS measures were significantly correlated (r=.515, p=.0009), but no significant association between R(2) and CPS was detected in the splenium (p=.409). LMWM R(2), but not SWM R(2), was a significant mediator of the relationship between age and CPS (p=.037).

Conclusions: In this very healthy elderly sample, age-related slowing in CPS is mediated by myelin breakdown in highly vulnerable late-myelinating regions but not in the splenium.
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http://dx.doi.org/10.1016/j.bandc.2012.09.006DOI Listing
February 2013

DTI tractography and white matter fiber tract characteristics in euthymic bipolar I patients and healthy control subjects.

Brain Imaging Behav 2013 Jun;7(2):129-39

Laboratory of Neuro Imaging LONI, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, 635 Charles E. Young Dr. S, Los Angeles, CA 90095, USA.

With the introduction of diffusion tensor imaging (DTI), structural differences in white matter (WM) architecture between psychiatric populations and healthy controls can be systematically observed and measured. In particular, DTI-tractography can be used to assess WM characteristics over the entire extent of WM tracts and aggregated fiber bundles. Using 64-direction DTI scanning in 27 participants with bipolar disorder (BD) and 26 age-and-gender-matched healthy control subjects, we compared relative length, density, and fractional anisotrophy (FA) of WM tracts involved in emotion regulation or theorized to be important neural components in BD neuropathology. We interactively isolated 22 known white matter tracts using region-of-interest placement (TrackVis software program) and then computed relative tract length, density, and integrity. BD subjects demonstrated significantly shorter WM tracts in the genu, body and splenium of the corpus callosum compared to healthy controls. Additionally, bipolar subjects exhibited reduced fiber density in the genu and body of the corpus callosum, and in the inferior longitudinal fasciculus bilaterally. In the left uncinate fasciculus, however, BD subjects exhibited significantly greater fiber density than healthy controls. There were no significant differences between groups in WM tract FA for those tracts that began and ended in the brain. The significance of differences in tract length and fiber density in BD is discussed.
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http://dx.doi.org/10.1007/s11682-012-9202-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572298PMC
June 2013

Multimodal magnetic resonance imaging assessment of white matter aging trajectories over the lifespan of healthy individuals.

Biol Psychiatry 2012 Dec 25;72(12):1026-34. Epub 2012 Sep 25.

Department of Psychiatry, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Background: Postmortem and volumetric imaging data suggest that brain myelination is a dynamic lifelong process that, in vulnerable late-myelinating regions, peaks in middle age. We examined whether known regional differences in axon size and age at myelination influence the timing and rates of development and degeneration/repair trajectories of white matter (WM) microstructure biomarkers.

Methods: Healthy subjects (n = 171) 14-93 years of age were examined with transverse relaxation rate (R(2)) and four diffusion tensor imaging measures (fractional anisotropy [FA] and radial, axial, and mean diffusivity [RD, AxD, MD, respectively]) of frontal lobe, genu, and splenium of the corpus callosum WM (FWM, GWM, and SWM, respectively).

Results: Only R(2) reflected known levels of myelin content with high values in late-myelinating FWM and GWM regions and low ones in early-myelinating SWM. In FWM and GWM, all metrics except FA had significant quadratic components that peaked at different ages (R(2) < RD < MD < AxD), with FWM peaking later than GWM. Factor analysis revealed that, although they defined different factors, R(2) and RD were the metrics most closely associated with each other and differed from AxD, which entered into a third factor.

Conclusions: The R(2) and RD trajectories were most dynamic in late-myelinating regions and reflect age-related differences in myelination, whereas AxD reflects axonal size and extra-axonal space. The FA and MD had limited specificity. The data suggest that the healthy adult brain undergoes continual change driven by development and repair processes devoted to creating and maintaining synchronous function among neural networks on which optimal cognition and behavior depend.
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http://dx.doi.org/10.1016/j.biopsych.2012.07.010DOI Listing
December 2012

Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia.

Schizophr Res 2012 Sep 17;140(1-3):122-8. Epub 2012 Jul 17.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Context: Imaging and post-mortem studies suggest that frontal lobe intracortical myelination is dysregulated in schizophrenia (SZ). Prior MRI studies suggested that early in the treatment of SZ, antipsychotic medications initially increase frontal lobe intracortical myelin (ICM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of ICM decline in chronic SZ is due to medication non-adherence or pharmacokinetics, it may be modifiable by long acting injection (LAI) formulations.

Objectives: Assess the effect of risperidone formulation on the ICM trajectory during a six-month randomized trial of LAI (RLAI) versus oral (RisO) in first-episode SZ subjects.

Design: Two groups of SZ subjects (RLAI, N=9; and RisO, N=13) matched on pre-randomization oral medication exposure were prospectively examined at baseline and 6 months later, along with 12 healthy controls (HCs). Frontal lobe ICM volume was assessed using inversion recovery (IR) and proton density (PD) MRI images. Medication adherence was tracked.

Main Outcome Measure: ICM volume change scores were adjusted for the change in the HCs.

Results: ICM volume increased significantly (p=.005) in RLAI and non-significantly (p=.39) in the RisO groups compared with that of the healthy controls. A differential between-group treatment effect was at a trend level (p=.093). SZ subjects receiving RLAI had better medication adherence and more ICM increases (chi-square p<.05).

Conclusions: The results suggest that RLAI may promote ICM development in first-episode SZ patients. Better adherence and/or pharmacokinetics provided by LAI may modify the ICM trajectory. In vivo MRI myelination measures can help clarify pharmacotherapeutic mechanisms of action.
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http://dx.doi.org/10.1016/j.schres.2012.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567927PMC
September 2012

Mood-state effects on amygdala volume in bipolar disorder.

J Affect Disord 2012 Aug 21;139(3):298-301. Epub 2012 Apr 21.

Laboratory of Neuro Imaging, Dept. of Neurology, UCLA School of Medicine, Los Angeles, CA, USA.

Background: Prior structural neuroimaging studies of the amygdala in patients with bipolar disorder have reported higher or lower volumes, or no difference relative to healthy controls. These inconsistent findings may have resulted from combining subjects in different mood states. The prefrontal cortex has recently been reported to have a lower volume in depressed versus euthymic bipolar patients. Here we examined whether similar mood state-dependent volumetric differences are detectable in the amygdala.

Methods: Forty subjects, including 28 with bipolar disorder type I (12 depressed and 16 euthymic), and 12 healthy comparison subjects were scanned on a 3T magnetic resonance image (MRI) scanner. Amygdala volumes were manually traced and compared across subject groups, adjusting for sex and total brain volume.

Results: Statistical analyses found a significant effect of mood state and hemisphere on amygdala volume. Subsequent comparisons revealed that amygdala volumes were significantly lower in the depressed bipolar group compared to both the euthymic bipolar (p=0.005) and healthy control (p=0.043) groups.

Limitations: Our study was cross-sectional and some patients were medicated.

Conclusions: Our results suggest that mood state influences amygdala volume in subjects with bipolar disorder. Future studies that replicate these findings in unmedicated patient samples scanned longitudinally are needed.
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http://dx.doi.org/10.1016/j.jad.2012.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372678PMC
August 2012

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.

Proc Natl Acad Sci U S A 2012 Mar 16;109(10):3985-90. Epub 2012 Feb 16.

Medical Scientist Training Program, University of California at San Diego, La Jolla, CA 92093, USA.

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.
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http://dx.doi.org/10.1073/pnas.1105829109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309762PMC
March 2012

Depressive symptoms in mild cognitive impairment predict greater atrophy in Alzheimer's disease-related regions.

Biol Psychiatry 2012 May 8;71(9):814-21. Epub 2012 Feb 8.

Department of Neurology, David Geffen School of Medicine at University of California Los Angeles, USA.

Background: Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and may be a marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Thus, we examined the neuroanatomical changes associated with depressive symptoms in MCI.

Methods: Two-hundred forty-three MCI subjects from the Alzheimer's Disease Neuroimaging Initiative who had brain magnetic resonance imaging scans at baseline and 2-year follow-up were classified into depressed (n = 44), nondepressed with other neuropsychiatric symptoms (n = 93), and no-symptom (NOSYMP; n = 106) groups based on the Neuropsychiatric Inventory Questionnaire. Tensor-based morphometry was used to create individual three-dimensional maps of 2-year brain changes that were compared between groups.

Results: Depressed subjects had more frontal (p = .024), parietal (p = .030), and temporal (p = .038) white matter atrophy than NOSYMP subjects. Those whose depressive symptoms persisted over 2 years also had higher conversion to AD and more decline on measures of global cognition, language, and executive functioning compared with stable NOSYMP subjects. Nondepressed with other neuropsychiatric symptoms and NOSYMP groups exhibited no differences in rates of atrophy.

Conclusions: Depressive symptoms were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes, including prodromal AD, and may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD.
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http://dx.doi.org/10.1016/j.biopsych.2011.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322258PMC
May 2012

Neuroglialpharmacology: myelination as a shared mechanism of action of psychotropic treatments.

Authors:
George Bartzokis

Neuropharmacology 2012 Jun 28;62(7):2137-53. Epub 2012 Jan 28.

Department of Psychiatry, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Current psychiatric diagnostic schema segregate symptom clusters into discrete entities, however, large proportions of patients suffer from comorbid conditions that fit neither diagnostic nor therapeutic schema. Similarly, psychotropic treatments ranging from lithium and antipsychotics to serotonin reuptake inhibitors (SSRIs) and acetylcholinesterase inhibitors have been shown to be efficacious in a wide spectrum of psychiatric disorders ranging from autism, schizophrenia (SZ), depression, and bipolar disorder (BD) to Alzheimer's disease (AD). This apparent lack of specificity suggests that psychiatric symptoms as well as treatments may share aspects of pathophysiology and mechanisms of action that defy current symptom-based diagnostic and neuron-based therapeutic schema. A myelin-centered model of human brain function can help integrate these incongruities and provide novel insights into disease etiologies and treatment mechanisms. Available data are integrated herein to suggest that widely used psychotropic treatments ranging from antipsychotics and antidepressants to lithium and electroconvulsive therapy share complex signaling pathways such as Akt and glycogen synthase kinase-3 (GSK3) that affect myelination, its plasticity, and repair. These signaling pathways respond to neurotransmitters, neurotrophins, hormones, and nutrition, underlie intricate neuroglial communications, and may substantially contribute to the mechanisms of action and wide spectra of efficacy of current therapeutics by promoting myelination. Imaging and genetic technologies make it possible to safely and non-invasively test these hypotheses directly in humans and can help guide clinical trial efforts designed to correct myelination abnormalities. Such efforts may provide insights into novel avenues for treatment and prevention of some of the most prevalent and devastating human diseases.
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http://dx.doi.org/10.1016/j.neuropharm.2012.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586811PMC
June 2012

Cigarette smoking and white matter microstructure.

Psychopharmacology (Berl) 2012 May 4;221(2):285-95. Epub 2012 Jan 4.

Division of Child and Adolescent Psychiatry, UCLA Semel Institute for Neurosciences and Biobehavioral Studies, 760 Westwood Plaza #58-227A, Los Angeles, CA 90024-1759, USA.

Rationale: Diffusion tensor imaging has been used before in testing associations between cigarette smoking and white matter integrity, with inconsistent results. Published reports indicate higher fractional anisotropy (FA, a measure of linear water diffusion) in some brain regions and lower FA in others in adult smokers compared to nonsmokers. Adolescent smokers exhibited elevated FA at several brain regions and a positive correlation of FA in the genu corpus callosum with exposure to smoking (pack-years).

Objective: To help resolve prior discrepancies, we studied adults, sampling multiple brain regions, and testing for relationships to clinical features of nicotine dependence and exposure to smoking.

Methods: Brain MRI scans (1.5 T) were acquired, and FA and apparent diffusion coefficient (ADC, a measure of random diffusion) were assayed in corpus callosum and prefrontal white matter, corona radiata, internal capsule, cingulum bundle, and hippocampal perforant fibers in 18 smokers (33.7 ± 7.9 years of age) and 18 age- and gender-matched nonsmokers.

Results: ADC showed no group difference, but smokers had higher (4.3-21.1%) FA than nonsmokers. The differences were significant in right prefrontal white matter, cingulum, and genu corpus callosum. FA in several regions was negatively correlated with nicotine dependence or cigarettes/day.

Conclusions: Combined with earlier findings, these results suggest a model of changing trajectories whereby FA is higher with tobacco exposure during adolescence and declines with continued smoking in adulthood. This notion is supported by the observation that, at multiple sampling sites, participants who had started smoking earlier in life had higher FA than those who had started later.
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http://dx.doi.org/10.1007/s00213-011-2621-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111107PMC
May 2012

Age-related slowing in cognitive processing speed is associated with myelin integrity in a very healthy elderly sample.

J Clin Exp Neuropsychol 2011 Dec 26;33(10):1059-68. Epub 2011 Aug 26.

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Performance on measures of cognitive processing speed (CPS) slows with age, but the biological basis associated with this cognitive phenomenon remains incompletely understood. We assessed the hypothesis that the age-related slowing in CPS is associated with myelin breakdown in late-myelinating regions in a very healthy elderly population. An in vivo magnetic resonance imaging (MRI) biomarker of myelin integrity was obtained from the prefrontal lobe white matter and the genu of the corpus callosum for 152 healthy elderly adults. These regions myelinate later in brain development and are more vulnerable to breakdown due to the effects of normal aging. To evaluate regional specificity, we also assessed the splenium of the corpus callosum as a comparison region, which myelinates early in development and primarily contains axons involved in visual processing. The measure of myelin integrity was significantly correlated with CPS in highly vulnerable late-myelinating regions but not in the splenium. These results have implications for the neurobiology of the cognitive changes associated with brain aging.
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http://dx.doi.org/10.1080/13803395.2011.595397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269444PMC
December 2011

Survey of protocols for the manual segmentation of the hippocampus: preparatory steps towards a joint EADC-ADNI harmonized protocol.

J Alzheimers Dis 2011 ;26 Suppl 3:61-75

LENITEM-Laboratory of Epidemiology, Neuroimaging and Telemedicine IRCCS - S. Giovanni di Dio - Fatebenefratelli Brescia, Italy.

Manual segmentation from magnetic resonance imaging (MR) is the gold standard for evaluating hippocampal atrophy in Alzheimer's disease (AD). Nonetheless, different segmentation protocols provide up to 2.5-fold volume differences. Here we surveyed the most frequently used segmentation protocols in the AD literature as a preliminary step for international harmonization. The anatomical landmarks (anteriormost and posteriormost slices, superior, inferior, medial, and lateral borders) were identified from 12 published protocols for hippocampal manual segmentation ([Abbreviation] first author, publication year: [B] Bartzokis, 1998; [C] Convit, 1997; [dTM] deToledo-Morrell, 2004; [H] Haller, 1997; [J] Jack, 1994; [K] Killiany, 1993; [L] Lehericy, 1994; [M] Malykhin, 2007; [Pa] Pantel, 2000; [Pr] Pruessner, 2000; [S] Soininen, 1994; [W] Watson, 1992). The hippocampi of one healthy control and one AD patient taken from the 1.5T MR ADNI database were segmented by a single rater according to each protocol. The accuracy of the protocols' interpretation and translation into practice was checked with lead authors of protocols through individual interactive web conferences. Semantically harmonized landmarks and differences were then extracted, regarding: (a) the posteriormost slice, protocol [B] being the most restrictive, and [H, M, Pa, Pr, S] the most inclusive; (b) inclusion [C, dTM, J, L, M, Pr, W] or exclusion [B, H, K, Pa, S] of alveus/fimbria; (c) separation from the parahippocampal gyrus, [C] being the most restrictive, [B, dTM, H, J, Pa, S] the most inclusive. There were no substantial differences in the definition of the anteriormost slice. This survey will allow us to operationalize differences among protocols into tracing units, measure their impact on the repeatability and diagnostic accuracy of manual hippocampal segmentation, and finally develop a harmonized protocol.
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http://dx.doi.org/10.3233/JAD-2011-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829626PMC
February 2012

Premenopausal hysterectomy is associated with increased brain ferritin iron.

Neurobiol Aging 2012 Sep 16;33(9):1950-8. Epub 2011 Sep 16.

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Iron is essential for triggering oligodendrocytes to myelinate, however, in gray matter (GM) iron increases with age and is associated with age-related degenerative brain diseases. Women have lower iron levels than men, both in the periphery and in the brain, particularly in white matter (WM), possibly due to iron loss through menstruation. We tested the hypothesis that hysterectomy could increase WM iron levels. We assessed 3 WM and 5 gray matter regions in 39 postmenopausal women, of whom 15 had premenopausal hysterectomy, utilizing a validated magnetic resonance imaging technique called field-dependent R2 increase (FDRI) that quantifies ferritin iron. A group of 54 matched male subjects was included for comparison. Amongst women, hysterectomy was associated with significantly higher frontal lobe WM iron. Men had higher iron levels than women without hysterectomy in 3 brain regions but did not differ from women with hysterectomy in any region. The results suggest that menstruation-associated blood loss is a source of gender differences in brain iron. It is possible that brain iron can be influenced by peripheral iron levels and may thus be a modifiable risk factor for age-related degenerative diseases.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245348PMC
September 2012

Long acting injection versus oral risperidone in first-episode schizophrenia: differential impact on white matter myelination trajectory.

Schizophr Res 2011 Oct 20;132(1):35-41. Epub 2011 Jul 20.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at UCLA, Los Angeles, California, United States.

Context: Imaging and post-mortem studies provide converging evidence that subjects with schizophrenia (SZ) have a dysregulated trajectory of frontal lobe myelination. Prior MRI studies suggested that early in treatment of SZ, antipsychotic medications initially increase frontal lobe white matter (WM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of WM decline associated with chronic disease may be due to medication non-adherence, it may be modifiable by long acting injection (LAI) formulations.

Objectives: Examine the impact of antipsychotic formulation on the myelination trajectory during a randomized six-month trial of LAI risperidone (RLAI) versus oral risperidone (RisO) in first-episode SZ subjects.

Design: Two groups of SZ subjects (RLAI, N=11; and RisO, N=13) that were matched in pre-randomization oral medication exposure and 14 healthy controls (HCs) were prospectively examined. Frontal lobe WM volume was estimated using inversion recovery (IR) MRI images. A brief neuropsychological battery that focused on reaction times was performed at the end of the study.

Main Outcome Measure: WM volume change scores.

Results: WM volume remained stable in the RLAI and decreased significantly in the RisO groups resulting in a significant differential treatment effect, while the HC had a WM change intermediate and not significantly different from the two SZ groups. WM increase was associated with faster reaction times in tests involving frontal lobe function.

Conclusions: The results suggest that RLAI may improve the trajectory of myelination in first-episode patients and have a beneficial impact on cognitive performance. Better adherence provided by LAI may underlie the modified trajectory of myelin development. In vivo MRI biomarkers of myelination can help clarify mechanisms of action of treatment interventions.
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http://dx.doi.org/10.1016/j.schres.2011.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172389PMC
October 2011

Neuroglialpharmacology: white matter pathophysiologies and psychiatric treatments.

Authors:
George Bartzokis

Front Biosci (Landmark Ed) 2011 Jun 1;16:2695-733. Epub 2011 Jun 1.

Department of Psychiatry, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Psychotropic treatments such as second generation or atypical antipsychotics are efficacious in a wide spectrum of psychiatric disorders ranging from schizophrenia to depression, bipolar disorder, and autism. These treatments are associated with peripheral metabolic derangements that are often also present in drug-naive patients. Furthermore, altering lipid composition/levels (with omega 3 fatty acids) and ameliorating oxidative toxicities may treat/prevent disease. The above observations are reexamined from the perspective of a myelin-centered model of the human brain. The model proposes that the human brain's extensive myelination required higher metabolic resources that caused evolutionary adaptations resulting in our quadratic (inverted U) myelination trajectory that peaks in the sixth decade of life. It further proposes that optimal brain function depends on exquisite action potential synchronization that myelin makes possible and that myelin's exceptional vulnerability to subtle metabolic/oxidative abnormalities may promote both developmental and degenerative diseases. Available data are integrated herein to suggest that widely used psychotropic treatments have under-appreciated CNS metabolic and neurotransmitter effects on myelination, its plasticity, and repair that may substantially contribute to their mechanisms of action.
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http://dx.doi.org/10.2741/3881DOI Listing
June 2011

Gender and iron genes may modify associations between brain iron and memory in healthy aging.

Neuropsychopharmacology 2011 Jun 9;36(7):1375-84. Epub 2011 Mar 9.

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-6968, USA.

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON-) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON- status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=-0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON- group (r=-0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.
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http://dx.doi.org/10.1038/npp.2011.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096807PMC
June 2011

Oligodendrocytes in schizophrenia.

Schizophr Res Treatment 2011 18;2011:249768. Epub 2011 Sep 18.

Department of Anatomy, Southern Illinois University Carbondale, Carbondale, IL 62901, USA.

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http://dx.doi.org/10.1155/2011/249768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420671PMC
August 2012
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