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Bartzokis G.,University of California at Los Angeles | Bartzokis G.,Laboratory of Neuroimaging | Bartzokis G.,Greater Los Angeles VA Healthcare System | Lu P.H.,University of California at Los Angeles | And 13 more authors.
Schizophrenia Research | Year: 2012

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. © 2012 Elsevier B.V.


Szeszko P.R.,Feinstein Institute for Medical Research | Szeszko P.R.,Zucker Hillside Hospital | Szeszko P.R.,Yeshiva University | Narr K.L.,Laboratory of Neuroimaging | And 12 more authors.
Schizophrenia Bulletin | Year: 2012

Identifying neurobiological predictors of response to antipsychotics in patients with schizophrenia is a critical goal of translational psychiatry. Few studies, however, have investigated the relationship between indices of brain structure and treatment response in the context of a controlled clinical trial. In this study, we sought to identify magnetic resonance (MR) imaging measures of the brain that predict treatment response in patients experiencing a first-episode of schizophrenia. Structural MR imaging scans were acquired in 39 patients experiencing a first-episode of schizophrenia with minimal or no prior exposure to antipsychotics participating in a double-blind 16-week clinical trial comparing the efficacy of risperidone vs olanzapine. Twenty-five patients were classified as responders by meeting operationally defined treatment response criteria on 2 consecutive study visits. Fourteen patients never responded to antipsychotic medication at any point during the clinical trial. MR imaging scans were also acquired in 45 age-and sex-matched healthy volunteers. Cortical pattern matching methods were used to compare cortical thickness and asymmetry measures among groups. Statistical mapping results, confirmed by permutation testing, indicated that responders had greater cortical thickness in occipital regions and greater frontal cortical asymmetry compared with nonresponders. Moreover, among responders, greater thickness in temporal regions was associated with less time to respond. Our findings are consistent with the hypothesis that plasticity and cortical thickness may be more preserved in responders and that MR imaging may assist in the prediction of antipsychotic drug response in patients experiencing a first-episode of schizophrenia. © 2010 The Author.


Lopes S.L.P.C.,São Paulo State University | Costa A.L.F.,City University of Sao Paulo | Cruz A.D.,Federal University of Fluminense | Li L.M.,Laboratory of Neuroimaging | De Almeida S.M.,University of Campinas
Dentomaxillofacial Radiology | Year: 2012

Objective: The aim of the present study was to describe the clinical and MRI findings of the temporomandibular joint (TMJ) in patients with major depressive disorders (MDDs) of the non-psychotic type. Methods: 40 patients (80 TMJs) who were diagnosed as having MDDs were selected for this study. The clinical examination of the TMJs was conducted according to the research diagnostic criteria and temporomandibular disorders (TMDs). The MRIs were obtained bilaterally in each patient with axial, parasagittal and paracoronal sections within a real-time dynamic sequence. Two trained oral radiologists assessed all images. For statistical analyses, Fisher's exact test and χ 2 test were applied (α 5 0.05). Results: Migraine was reported in 52.5% of subjects. Considering disc position, statistically significant differences between opening patterns with and without alteration (p=0.00) and between present and absent joint noises (p=0.00) were found. Regarding muscular pain, patients with and without abnormalities in disc function and patients with and without abnormalities in disc position were not statistically significant (p=0.42 and p=0.40, respectively). Significant differences between mandibular pathway with and without abnormalities (p50.00) and between present and absent joint noises (p=0.00) were observed. Conclusion: Based on the preliminary results observed by clinical and MRI examination of the TMJ, no direct relationship could be determined between MDDs and TMDs. © 2012 The British Institute of Radiology.


Altshuler L.L.,West Los Angeles Healthcare Center | Altshuler L.L.,University of California at Los Angeles | Abulseoud O.A.,University of Southern California | Foland-Ross L.,Laboratory of Neuroimaging | And 7 more authors.
Bipolar Disorders | Year: 2010

Objectives: Several magnetic resonance imaging studies have found changes in amygdala volumes in adults with mood disorders. The cellular basis for these changes has not been explored in detail. Specifically, it is not known whether differences in the density and/or volume of neurons or glial cells contribute to tissue volume changes seen on magnetic resonance images. Methods: Postmortem amygdala samples were obtained from the Stanley Foundation Neuropathology Consortium from subjects diagnosed with bipolar disorder (n = 10), major depressive disorder (n = 11), and schizophrenia (n = 9), and from normal controls (n = 14). Samples were first stained with glial fibrillary acidic protein (GFAP) and counter-stained with hematoxylin to ascertain neuron and glia (astrocyte) densities. Results: No significant differences in neuronal densities were found between groups. However, a reduction in the density of GFAP immunoreactive astrocytes was observed in the amygdala of subjects with major depressive disorder compared to the bipolar disorder, schizophrenia, and normal control postmortem samples. Conclusions: A decrease in density of GFAP immunoreactive astrocytes in the amygdala of depressed subjects is consistent with prior histologic reports and might contribute to amygdala volume reductions reported in several in vivo neuroimaging studies. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S.


Bartzokis G.,University of California at Los Angeles | Bartzokis G.,Laboratory of Neuroimaging | Bartzokis G.,Greater Los Angeles VA Healthcare System | Lu P.H.,University of California at Los Angeles | And 11 more authors.
Schizophrenia Research | Year: 2011

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. © 2011.


Raven E.P.,University of California at Los Angeles | Lu P.H.,University of California at Los Angeles | Tishler T.A.,University of California at Los Angeles | Heydari P.,University of California at Los Angeles | And 3 more authors.
Journal of Alzheimer's Disease | Year: 2013

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. © 2013-IOS Press and the authors. All rights reserved.


Apostolova L.G.,Laboratory of NeuroImaging | Mosconi L.,New York University | Thompson P.M.,Laboratory of NeuroImaging | Green A.E.,Laboratory of NeuroImaging | And 5 more authors.
Neurobiology of Aging | Year: 2010

Atrophic changes of the hippocampus are typically regarded as an early sign of Alzheimer's dementia (AD). Using the radial distance atrophy mapping approach, we compared the longitudinal MRI data of 10 cognitively normal elderly subjects who remained normal at 3-year and 6-year follow-up (NL-NL) and 7 cognitively normal elderly subjects who were diagnosed with mild cognitive impairment (MCI) 2.8 (range 2.0-3.9) and with AD 6.8 years (range 6.1-8.2) after baseline (NL-MCIAD). 3D statistical maps revealed greater hippocampal atrophy in the NL-MCIAD relative to the NL-NL group at baseline (left p=0.05; right p=0.06) corresponding to 10-15% CA1, and 10-25% subicular atrophy, and bilateral differences at 3-year follow-up (left p=0.001, right p<0.02) corresponding to 10-30% subicular, 10-20% CA1, and 10-20% newly developed CA2-3 atrophy. This preliminary study suggests that excess CA1 and subicular atrophy is present in cognitively normal individuals predestined to decline to amnestic MCI, while progressive involvement of the CA1 and subiculum, and atrophy spreading to the CA2-3 subfield in amnestic MCI, suggests future diagnosis of AD. © 2008 Elsevier Inc.


Bartzokis G.,University of California at Los Angeles | Bartzokis G.,Laboratory of Neuroimaging | Bartzokis G.,Greater Los Angeles VA Healthcare System | Lu P.H.,University of California at Los Angeles | And 12 more authors.
Neurobiology of Aging | Year: 2010

Objective: Myelination of the human brain results in roughly quadratic trajectories of myelin content and integrity, reaching a maximum in mid-life and then declining in older age. This trajectory is most evident in vulnerable later myelinating association regions such as frontal lobes and may be the biological substrate for similar trajectories of cognitive processing speed. Speed of movement, such as maximal finger tapping speed (FTS), requires high-frequency action potential (AP) bursts and is associated with myelin integrity. We tested the hypothesis that the age-related trajectory of FTS is related to brain myelin integrity. Methods: A sensitive in vivo MRI biomarker of myelin integrity (calculated transverse relaxation rates (R 2)) of frontal lobe white matter (FLwm) was measured in a sample of very healthy males (N=72) between 23 and 80 years of age. To assess specificity, R 2 of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured. Results: FLwm R 2 and FTS measures were significantly correlated (r=.45, p<0001) with no association noted in the early-myelinating region (splenium). Both FLwm R 2 and FTS had significantly quadratic lifespan trajectories that were virtually indistinguishable and both reached a peak at 39 years of age and declined with an accelerating trajectory thereafter. Conclusions: The results suggest that in this very healthy male sample, maximum motor speed requiring high-frequency AP burst may depend on brain myelin integrity. To the extent that the FLwm changes assessed by R 2 contribute to an age-related reduction in AP burst frequency, it is possible that other brain functions dependent on AP bursts may also be affected. Non-invasive measures of myelin integrity together with testing of basic measures of processing speed may aid in developing and targeting anti-aging treatments to mitigate age-related functional declines. © 2008 Elsevier Inc.


Bartzokis G.,University of California at Los Angeles | Bartzokis G.,Laboratory of Neuroimaging | Bartzokis G.,Greater Los Angeles VA Healthcare System | Lu P.H.,University of California at Los Angeles | And 13 more authors.
Neuropsychopharmacology | Year: 2011

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 (r0.50, p0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON group (r0.49, p0.005) but not in the IRON group. Between-group interactions (p0.006) 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. © 2011 American College of Neuropsychopharmacology. All rights reserved.


PubMed | Laboratory of Neuroimaging
Type: Comparative Study | Journal: Dementia and geriatric cognitive disorders | Year: 2012

Dementia with Lewy bodies (DLB) and Alzheimers disease (AD) are the two most common neurodegenerative dementias. During the early stages, clinical distinction between them is often challenging. Our objective is to compare hippocampal atrophy patterns in mild AD and mild DLB. We hypothesized that DLB subjects have milder hippocampal atrophy relative to AD subjects.We analyzed the T1-weighted magnetic resonance imaging data from 113 subjects: 55 AD, 16 DLB and 42 cognitively normal elderly (normal controls, NC). Using the hippocampal radial distance technique and multiple linear regression, we analyzed the effect of clinical diagnosis on hippocampal radial distance, while adjusting for gender and age. Three-dimensional statistical maps were adjusted for multiple comparisons using permutation-based statistics with a threshold of p < 0.01.Compared to NC, AD exhibited significantly greater atrophy in the cornu ammonis (CA)1, CA2-3 and subicular regions bilaterally while DLB showed left-predominant atrophy in the CA1 region and subiculum. Compared directly, AD and DLB did not reveal statistically significant differences.Hippocampal atrophy, while present in mildly impaired DLB subjects, is less severe than atrophy seen in mildly impaired AD subjects, when compared to NC. Both groups show predominant atrophy of the CA1 subfield and subiculum.

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