Addiction Medicine Specialist, Neurologist (brain, nervous system), Psychiatrists
27 years of experience

Accepting new patients
Westwood
300 Ucla Medical Plz
Los Angeles, CA 90095
310-825-9989
Locations and availability (2)

Education ?

Medical School Score Rankings
Yale University (1983)
  • Currently 4 of 4 apples
Top 25%

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Schizophrenia
Appointments
Ronald Reagan Ucla Medical Center
Associations
American Board of Psychiatry and Neurology

Affiliations ?

Dr. Bartzokis is affiliated with 7 hospitals.

Hospital Affilations

Score

Rankings

  • UCLA Medical Center
    10833 Le Conte Ave, Los Angeles, CA 90095
    • Currently 4 of 4 crosses
    Top 25%
  • Santa Monica - UCLA Medical Center
    1250 16th St, Santa Monica, CA 90404
    • Currently 3 of 4 crosses
    Top 50%
  • Mattel Chldns Hosp. At Ucla
    10833 Le Conte Ave, Los Angeles, CA 90095
  • Stewart and Lynda Resnick Neuropsychiatric Hospital at UCLA
  • Veterans Affairs Greater Los Angeles Healthcare Center
    11301 Wilshire Blvd, Los Angeles, CA 90073
  • University of California - Ronald Reagan UCLA Medical Center
    757 Westwood Plz, Los Angeles, CA 90095
  • John Muir Medical Center-Concord Campus
  • Publications & Research

    Dr. Bartzokis has contributed to 82 publications.
    Title Amygdala Astrocyte Reduction in Subjects with Major Depressive Disorder but Not Bipolar Disorder.
    Date November 2010
    Journal Bipolar Disorders
    Excerpt

    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.

    Title Prevalent Iron Metabolism Gene Variants Associated with Increased Brain Ferritin Iron in Healthy Older Men.
    Date July 2010
    Journal Journal of Alzheimer's Disease : Jad
    Excerpt

    Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer's disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson's disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON- men (p=0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases.

    Title Therapeutics for Cognitive Aging.
    Date May 2010
    Journal Annals of the New York Academy of Sciences
    Excerpt

    This review summarizes the scientific talks presented at the conference "Therapeutics for Cognitive Aging," hosted by the New York Academy of Sciences and the Alzheimer's Drug Discovery Foundation on May 15, 2009. Attended by scientists from industry and academia, as well as by a number of lay people-approximately 200 in all-the conference specifically tackled the many aspects of developing therapeutic interventions for cognitive impairment. Discussion also focused on how to define cognitive aging and whether it should be considered a treatable, tractable disease.

    Title White-matter Abnormalities in Brain During Early Abstinence from Methamphetamine Abuse.
    Date April 2010
    Journal Psychopharmacology
    Excerpt

    Previous studies revealed microstructural abnormalities in prefrontal white matter and corpus callosum of long-term abstinent chronic methamphetamine abusers. In view of the importance of the early abstinence period in treatment retention, we compared 23 methamphetamine-dependent subjects abstinent from methamphetamine for 7-13 days with 18 healthy comparison subjects. As certain metabolic changes in the brain first manifest after early abstinence from methamphetamine, it is also possible that microstructural white-matter abnormalities are not yet present during early abstinence.

    Title Processing Speed is Correlated with Cerebral Health Markers in the Frontal Lobes As Quantified by Neuroimaging.
    Date February 2010
    Journal Neuroimage
    Excerpt

    We explored relationships between decline in cognitive processing speed (CPS) and change in frontal lobe MRI/MRS-based indices of cerebral integrity in 38 healthy adults (age 57-90 years). CPS was assessed using a battery of four timed neuropsychological tests: Grooved Pegboard, Coding, Symbol Digit Modalities Test and Category Fluency (Fruits and Furniture). The neuropsychological tests were factor analyzed to extract two components of CPS: psychomotor (PM) and psychophysical (PP). MRI-based indices of cerebral integrity included three cortical measurements per hemisphere (GM thickness, intergyral and sulcal spans) and two subcortical indices (fractional anisotropy (FA), measured using track-based spatial statistics (TBSS), and the volume of hyperintense WM (HWM)). MRS indices included levels of choline-containing compounds (GPC+PC), phosphocreatine plus creatine (PCr+Cr), and N-acetylaspartate (NAA), measured bilaterally in the frontal WM bundles. A substantial fraction of the variance in the PM-CPS (58%) was attributed to atrophic changes in frontal WM, observed as increases in sulcal span, declines in FA values and reductions in concentrations of NAA and choline-containing compounds. A smaller proportion (20%) of variance in the PP-CPS could be explained by bilateral increases in frontal sulcal span and increases in HWM volumes.

    Title In Vivo Evidence of Differential Impact of Typical and Atypical Antipsychotics on Intracortical Myelin in Adults with Schizophrenia.
    Date October 2009
    Journal Schizophrenia Research
    Excerpt

    Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination. The hypothesis that typical and atypical medications may differentially impact brain myelination in adults with schizophrenia was previously assessed with inversion recovery (IR) images. Increased white matter (WM) volume suggestive of increased myelination was detected in the patient group treated with an atypical antipsychotic compared to a typical one.

    Title Abuse of Amphetamines and Structural Abnormalities in the Brain.
    Date December 2008
    Journal Annals of the New York Academy of Sciences
    Excerpt

    We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetamines in utero. Evidence comes from studies that used a variety of techniques including manual tracing, pattern matching, voxel-based, tensor-based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3-4-methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine-rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occur in utero. Several forms of white matter abnormality are also common and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross-sectional designs, which cannot infer causality. Potential confounding influences include effects of pre existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain structure.

    Title The Alzheimer's Disease Neuroimaging Initiative (adni): Mri Methods.
    Date August 2008
    Journal Journal of Magnetic Resonance Imaging : Jmri
    Excerpt

    The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal multisite observational study of healthy elders, mild cognitive impairment (MCI), and Alzheimer's disease. Magnetic resonance imaging (MRI), (18F)-fluorodeoxyglucose positron emission tomography (FDG PET), urine serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical/psychometric assessments are acquired at multiple time points. All data will be cross-linked and made available to the general scientific community. The purpose of this report is to describe the MRI methods employed in ADNI. The ADNI MRI core established specifications that guided protocol development. A major effort was devoted to evaluating 3D T(1)-weighted sequences for morphometric analyses. Several options for this sequence were optimized for the relevant manufacturer platforms and then compared in a reduced-scale clinical trial. The protocol selected for the ADNI study includes: back-to-back 3D magnetization prepared rapid gradient echo (MP-RAGE) scans; B(1)-calibration scans when applicable; and an axial proton density-T(2) dual contrast (i.e., echo) fast spin echo/turbo spin echo (FSE/TSE) for pathology detection. ADNI MRI methods seek to maximize scientific utility while minimizing the burden placed on participants. The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom-based monitoring of all scanners could be used as a model for other multisite trials.

    Title Diagnosing Depression in Alzheimer Disease with the National Institute of Mental Health Provisional Criteria.
    Date August 2008
    Journal The American Journal of Geriatric Psychiatry : Official Journal of the American Association for Geriatric Psychiatry
    Excerpt

    OBJECTIVE: To compare the rates of depression in Alzheimer Disease (AD) determined using National Institute of Mental Health (NIMH) provisional criteria for depression in AD (NIMH-dAD) to those determined using other established depression assessment tools. DESIGN: Descriptive longitudinal cohort study. SETTING: The Alzheimer's Disease Research Centers of California. PARTICIPANTS: A cohort of 101 patients meeting NINDS-ADRDA criteria for possible/probable AD, intentionally selected to increase the frequency of depression at baseline. MEASUREMENTS: Depression was diagnosed at baseline and after 3 months using NIMH-dAD criteria and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I Disorders. Depressive symptoms also were assessed with the Cornell Scale for Depression in Dementia (CSDD), the Geriatric Depression Scale (GDS), and the Neuropsychiatric Inventory Questionnaire. RESULTS: The baseline frequency of depression using NIMH-dAD criteria (44%) was higher than that obtained using DSM-IV criteria for major depression (14%; Z = -5.50, df = 101, p <0.001) and major or minor depression (36%; Z = -2.86, df = 101, p = 0.021) or using established cut-offs for the CSDD (30%; Z = -2.86, df = 101, p = 0.004) or GDS (33%; Z = -2.04, df = 101, p = 0.041). The NIMH-dAD criteria correctly identified all patients meeting DSM-IV criteria for major depression, and correlated well with DSM-IV criteria for major or minor depression (kappa = 0.753, p <0.001), exhibiting 94% sensitivity and 85% specificity. The higher rates of depression found with NIMH-dAD criteria derived primarily from its less stringent requirements for the frequency and duration of symptoms. Remission rates at 3 months were similar across instruments. CONCLUSIONS: The NIMH-dAD criteria identify a greater proportion of AD patients as depressed than several other established tools.

    Title Apolipoprotein E Affects Both Myelin Breakdown and Cognition: Implications for Age-related Trajectories of Decline into Dementia.
    Date February 2008
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Age-related myelin breakdown is most evident in later-myelinating white matter (LMwm) brain regions. This process might degrade cognitive processing speed (CPS) underlying age-related cognitive decline and the predominance of age as a risk factor for Alzheimer's disease (AD). Apolipoprotein E (ApoE) 4 allele is the second most important AD risk factor. We tested the hypothesis that ApoE4 accelerates age-related slowing in CPS through the process of myelin breakdown. METHODS: Calculated transverse relaxation rates (R(2)), an indirect magnetic resonance imaging measure of myelin breakdown in LMwm, and measures of CPS were obtained in 22 ApoE4+ and 80 ApoE4-, healthy "younger-old" individuals. To assess specificity, contrasting early-myelinating white matter region and memory task were also examined. RESULTS: The CPS versus LMwm R(2) remained significant in the ApoE4+ group even after age was statistically adjusted (r = .65, p = .001) and differed from the correlation observed in the ApoE4- group (Fisher's z test = 3.22, p < .002). No significant associations were observed with the contrast region and memory task in either ApoE subgroup. CONCLUSIONS: A specific association between CPS and myelin breakdown in LMwm exists in asymptomatic "younger-old" individuals at increased genetic risk for AD. Although inferences of change over time and causality are limited by the cross-sectional study design, this finding lends support to the hypotheses that myelin breakdown underlies age-related slowing in CPS and that by altering the trajectory of myelin breakdown, ApoE alleles shift the age at onset of cognitive decline. Combined use of biomarkers and CPS measures might be useful in developing and targeting primary prevention treatments for AD.

    Title Myelin Breakdown and Iron Changes in Huntington's Disease: Pathogenesis and Treatment Implications.
    Date November 2007
    Journal Neurochemical Research
    Excerpt

    BACKGROUND: Postmortem and in vivo imaging data support the hypothesis that premature myelin breakdown and subsequent homeostatic remyelination attempts with increased oligodendrocyte and iron levels may contribute to Huntington's Disease (HD) pathogenesis and the symmetrical progress of neuronal loss from earlier-myelinating striatum to later-myelinating regions. A unique combination of in vivo tissue integrity and iron level assessments was used to examine the hypothesis. METHODS: A method that uses two Magnetic resonance imaging (MRI) instruments operating at different field-strengths was used to quantify the iron content of ferritin molecules (ferritin iron) as well as tissue integrity in eight regions in 11 HD and a matched group of 27 healthy control subjects. Three white matter regions were selected based on their myelination pattern (early to later-myelinating) and fiber composition. These were frontal lobe white matter (Fwm) and splenium and genu of the corpus callosum (Swm and Gwm). In addition, gray matter structures were also chosen based on their myelination pattern and fiber composition. Three striatum structures were assessed [caudate, putamen, and globus pallidus (C, P, and G)] as well as two comparison gray matter regions that myelinate later in development and are relatively spared in HD [Hippocampus (Hipp) and Thalamus (Th)]. RESULTS: Compared to healthy controls, HD ferritin iron levels were significantly increased in striatum C, P, and G, decreased in Fwm and Gwm, and were unchanged in Hipp, Th, and Swm. Loss of tissue integrity was observed in C, P, Fwm, and especially Swm but not Hipp, Th, G, or Gwm. This pattern of findings was largely preserved when a small subset of HD subjects early in the disease process was examined. CONCLUSIONS: The data suggest early in the HD process, myelin breakdown and changes in ferritin iron distribution underlie the pattern of regional toxicity observed in HD. Prospective studies are needed to verify myelin breakdown and increased iron levels are causal factors in HD pathogenesis. Tracking the effects of novel interventions that reduce myelin breakdown and iron accumulation in preclinical stages of HD could hasten the development of preventive treatments.

    Title Acetylcholinesterase Inhibitors May Improve Myelin Integrity.
    Date September 2007
    Journal Biological Psychiatry
    Excerpt

    Recent clinical trials have revealed that cholinergic treatments are efficacious in a wide spectrum of neuropsychiatric disorders that span the entire human lifespan and include disorders without cholinergic deficits. Furthermore, some clinical and epidemiological data suggest that cholinergic treatments have disease modifying/preventive effects. It is proposed that these observations can be usefully understood in a myelin-centered model of the human brain. The model proposes that the human brain's extensive myelination is the central evolutionary change that defines our uniqueness as a species and our unique vulnerability to highly prevalent neuropsychiatric disorders. Within the framework of this model the clinical, biochemical, and epidemiologic data can be reinterpreted to suggest that nonsynaptic effects of cholinergic treatments on the process of myelination and myelin repair contributes to their mechanism of action and especially to their disease modifying/preventive effects. The ability to test the model in human populations with safe and noninvasive imaging technologies makes it possible to undertake novel clinical trial efforts directed at primary prevention of some of the most prevalent and devastating of human disorders.

    Title Differential Effects of Typical and Atypical Antipsychotics on Brain Myelination in Schizophrenia.
    Date August 2007
    Journal Schizophrenia Research
    Excerpt

    CONTEXT: Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination even in adulthood. Atypical antipsychotics have been shown to have a wide spectrum of efficacy across multiple psychiatric diseases and to be particularly efficacious in treatment resistant cases of disorders such as schizophrenia. OBJECTIVE: To test the a priori hypothesis that antipsychotic medications may differentially impact frontal lobe myelination in patients with schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Participants ranged in age from 18-35 years, were all male, and were recruited by a single group of investigators using the same criteria. Two cohorts of subjects with schizophrenia early in their disease who were treated either with oral risperidone (Ris) or fluphenazine decanoate (Fd) were imaged in conjunction with cohorts of healthy controls. Each cohort was imaged using a different MRI instrument using identical imaging sequences. MAIN OUTCOME MEASURE: MRI measures of frontal lobe white matter volume. RESULTS: We estimated differences due to differences in the MRI instruments used in the two studies in the two healthy control groups matched to the patient samples, adjusting for age and other covariates. We then statistically removed those differences (which we assumed were due to instrument effects) from the data in the schizophrenia samples by subtraction. Relative to the differences seen in controls, the two groups of schizophrenic patients differed in their pattern of frontal lobe structure with the Ris-treated group having significantly larger white matter volume than the Fd group. CONCLUSIONS: The results suggest that the choice of antipsychotic treatment may differentially impact brain myelination in adults with schizophrenia. Prospective studies are needed to confirm this finding. MRI can be used to dissect subtle differences in brain tissue characteristics and thus could help clarify the effect of pharmacologic treatments on neurodevelopmental and pathologic processes in vivo.

    Title Diffusion Tensor Imaging in Preclinical and Presymptomatic Carriers of Familial Alzheimer's Disease Mutations.
    Date July 2007
    Journal Brain : a Journal of Neurology
    Excerpt

    Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating <1, n = 20) and presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white-matter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P = 0.002), hippocampal volume (P = 0.023) and mutation status (P = 0.032) significantly predicted fornix FA. We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease.

    Title Relationship Between White Matter Fractional Anisotropy and Other Indices of Cerebral Health in Normal Aging: Tract-based Spatial Statistics Study of Aging.
    Date June 2007
    Journal Neuroimage
    Excerpt

    White matter (WM) fractional anisotropy (FA) is thought to be related to WM integrity and decline in FA is often used as an index of decreasing WM health. However, the relationship of FA to other structural indices of cerebral health has not been well studied. We hypothesized that the decline in WM health will be associated with changes in several other indices of cerebral health. In this manuscript we studied the correlation between whole-brain/hemispheric/corpus callosum FA and gray matter (GM) thickness, sulcal span, and the volume of T2-hyperintense WM in a group of 31 healthy aging individuals (12 males/19 females) aged 57-82 years old. Individual subjects' FA measures were calculated from diffusion tracing imaging (DTI) data using tract-based spatial statistics--an approach specifically designed and validated for voxel-wise multi-subject FA analysis. Age-controlled correlation analysis showed that whole-brain average FA values were significantly and positively correlated with the subject's average GM thickness and negatively correlated with hyperintense WM volume. Intra-hemispheric correlations between FA and other measures of cerebral health had generally greater effect sizes than inter-hemispheric correction, with correlation between left FA and left GM thickness being the most significant (r=0.6, p<0.01). Regional analysis of FA values showed that late-myelinating fiber tracts of the genu of corpus callosum had higher association with other cerebral health indices. These data are consistent with the hypothesis that late-myelinating regions of the brain bear the brunt of age-related degenerative changes.

    Title Exploratory Voxel-based Analysis of Diffusion Indices and Hemispheric Asymmetry in Normal Aging.
    Date April 2007
    Journal Magnetic Resonance Imaging
    Excerpt

    Age-related microstructural changes in brain white matter can be studied by utilizing indices derived from diffusion tensor imaging (DTI): apparent diffusion coefficient (ADC) and fractional anisotropy (FA). The objective of this study is to examine alterations in FA and ADC by employing exploratory voxel-based analysis (VBA) and region(s) of interest (ROI)-based analysis. A highly nonlinear registration algorithm was used to align the ADC and FA image volumes of different subjects to perform accurate voxel-level statistics for two age groups, as well as for hemispheric asymmetry for both age groups. VBA shows significant age-related decline in FA with frontal predominance (frontal white matter, and genu and anterior body of the corpus callosum), superior portions of a splenium and highly oriented fibers of the posterior limb of the internal capsule and the anterior and posterior limbs of the external capsule. Hemispheric asymmetry of FA, as assessed by VBA, showed that for the young-age group, significant right-greater-than-left asymmetry exists in the genu, splenium and body of the corpus callosum and that left-greater-than-right asymmetry exists in the anterior limb of the external capsule and in the posterior limb of the internal capsule, thalamus, cerebral peduncle and temporal-parietal regions. VBA of the hemispheric asymmetry of the middle-age group revealed much less asymmetry. Regions showing age-related changes and hemispheric asymmetry from VBA were, for a majority of the findings, in conformance with ROI analysis and with the known pattern of development and age-related degradation of fiber tracks. The study shows the feasibility of the VBA of DTI indices for exploratory investigations of subtle differences in population cohorts, especially when findings are not localized and/or known a priori.

    Title Brain Ferritin Iron May Influence Age- and Gender-related Risks of Neurodegeneration.
    Date February 2007
    Journal Neurobiology of Aging
    Excerpt

    BACKGROUND: Brain iron promotes oxidative damage and protein oligomerization that result in highly prevalent age-related proteinopathies such as Alzheimer's disease (AD), Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB). Men are more likely to develop such diseases at earlier ages than women but brain iron levels increase with age in both genders. We hypothesized that brain iron may influence both the age- and gender-related risks of developing these diseases. METHODS: The amount of iron in ferritin molecules (ferritin iron) was measured in vivo with MRI by utilizing the field dependent relaxation rate increase (FDRI) method. Ferritin iron was measured in four subcortical nuclei [caudate (C), putamen (P), globus pallidus (G), thalamus (T)], three white matter regions [frontal lobe (Fwm), genu and splenium of the corpus callosum (Gwm, Swm)] and hippocampus (Hipp) in 165 healthy adults aged 19-82. RESULTS: There was a high correlation (r>0.99) between published post-mortem brain iron levels and FDRI. There were significant age-related changes in ferritin iron (increases in Hipp, C, P, G, and decreases in Fwm). Women had significantly lower ferritin iron than men in five regions (C, T, Fwm, Gwm, Swm). CONCLUSIONS: This is the first demonstration of gender differences in brain ferritin iron levels. It is possible that brain iron accumulation is a risk factor that can be modified. MRI provides the opportunity to assess brain iron levels in vivo and may be useful in targeting individuals or groups for preventive therapeutic interventions.

    Title Variation in Neurophysiological Function and Evidence of Quantitative Electroencephalogram Discordance: Predicting Cocaine-dependent Treatment Attrition.
    Date September 2006
    Journal The Journal of Neuropsychiatry and Clinical Neurosciences
    Excerpt

    Cocaine treatment trials suffer from a high rate of attrition. We examined pretreatment neurophysiological factors to identify participants at greatest risk. Twenty-five participants were divided into concordant and discordant groups following electroencephalogram (EEG) measures recorded prior to a double-blind, placebo-controlled treatment trial. Three possible outcomes were examined: successful completion, dropout, and removal. Concordant (high perfusion correlate) participants had an 85% rate of successful completion, while discordant participants had a 15% rate of successful completion. Twenty-five percent of dropouts and 50% of participants removed were discordant (low perfusion correlate), while only 25% of those who completed were discordant. Failure to complete the trial was not explained by depression, craving, benzoylecgonine levels or quantitative electroencephalogram (QEEG) power; thus cordance may help identify attrition risk.

    Title Neuroanatomical Correlates of Formal Thought Disorder in Schizophrenia.
    Date April 2006
    Journal Cognitive Neuropsychiatry
    Excerpt

    INTRODUCTION: We attempted to extend findings of a relationship between formal thought disorder and left superior temporal gyrus (STG) volume in schizophrenia by examining two indices of formal thought disorder. METHODS: Three brain regions of interest were selected from magnetic resonance imaging slices in 15 young, right-handed, male schizophrenia patients: the STG, the anterior hippocampus, and the amygdala. Thought disorder was assessed using the Bizarre-Idiosyncratic Thinking (BIZ) scale, a sensitive measure of formal thought disorder based on responses to a standard set of stimuli, and the BPRS Conceptual Disorganization item, a global rating based on a clinical interview. RESULTS: BIZ ratings of thought disorder were significantly correlated with the left STG volume (Spearman r = -.73) and with the right STG volume (Spearman r = -.58). BIZ ratings were not significantly correlated with either the left or right anterior hippocampus or amygdala volumes. The BPRS Conceptual Disorganisation rating was not significantly related to the STG, anterior hippocampus, or amygdala volumes. CONCLUSIONS: This study confirms the previously reported association between the left STG and formal thought disorder, and suggests that detection of this relationship may be facilitated by use of highly sensitive formal thought disorder assessments.

    Title Apolipoprotein E Genotype and Age-related Myelin Breakdown in Healthy Individuals: Implications for Cognitive Decline and Dementia.
    Date February 2006
    Journal Archives of General Psychiatry
    Excerpt

    CONTEXT: Apolipoprotein E (APOE) genotype is the most influential Alzheimer disease (AD) risk factor after advanced age. The APOE4 alleles decrease and the APOE2 alleles increase age at onset of AD. Human and nonhuman primate data suggest that in midlife, the structural integrity of myelin sheaths begins breaking down, with an accelerating age-related trajectory most evident in the brain's later-myelinating association regions. This may result in a progressive "disconnection" of widely distributed neural networks that may underlie the age risk factor for AD. OBJECTIVE: To assess, using magnetic resonance imaging, whether the shift in age at onset of AD observed with the APOE genotype is associated with the trajectory of age-related myelin breakdown. DESIGN: Cross-sectional. SETTING: Metropolitan university medical center. PARTICIPANTS: Healthy individuals (N = 104) aged 55 to 75 years who underwent genotyping for APOE. MAIN OUTCOME MEASURES: Calculated transverse relaxation rates, an indirect measure of white matter structural integrity, for late-myelinating frontal lobe white matter (Fwm) and early- and later-myelinating regions of the corpus callosum, the splenium (Swm) and the genu (Gwm). RESULTS: The presence of the protective APOE2 allele was associated with significantly higher relaxation rates in Fwm and Gwm but not in Swm. Furthermore, APOE status impacted the trajectory of age-related myelin breakdown in late-myelinating regions (Fwm and Gwm) but not in Swm. In Fwm and Gwm, APOE4+ individuals had a steeper slope of decline in relaxation rates with age than APOE2+ individuals; those with APOE3/3 alleles had an intermediate slope. CONCLUSIONS: In later-myelinating regions, the severity and rate of myelin breakdown in healthy older individuals are associated with APOE status and support the hypothesis that this process may contribute to age at onset of AD. Combining APOE status with noninvasive measures of myelin breakdown may be useful in assessing treatment strategies for the primary prevention of AD.

    Title Ambulatory Blood Pressure and the Brain: a 5-year Follow-up.
    Date December 2005
    Journal Neurology
    Excerpt

    OBJECTIVE: To determine if initial values of casual and ambulatory systolic blood pressure (SBP) predict white matter hyperintensities, insular subcortex hyperintensities, and brain atrophy 5 years later in a group of healthy elderly individuals. METHODS: The authors studied 155 healthy men and women, aged 55 to 79 years. Two 24-hour ambulatory blood pressure (BP) sessions assessed BP level and variability during waking and sleep. Hyperintensities and total brain volume were quantified by MRI. Procedures were repeated 5 years later in 78% (121) of subjects. RESULTS: Hyperintensities and brain atrophy increased over time, with greater increases among older subjects. The presence of increased BP level and variability initially and again 5 years later had negative consequences for the brain. Independent of age, the greater the initial SBP, the greater the likelihood that individuals would have severe white matter hyperintensities after 5 years. Also, elevated casual SBP was associated with severe insular subcortex hyperintensities and greater SBP sleep variability with increased brain atrophy. CONCLUSIONS: Among healthy elderly individuals whose initial, average, casual blood pressure (BP) was relatively low (116.9/71.1 mm Hg), small increases in casual and 24-hour ambulatory BP measures were associated with greater brain atrophy and subcortical lesions after 5 years.

    Title Increased Amygdala Activation During Mania: a Functional Magnetic Resonance Imaging Study.
    Date August 2005
    Journal The American Journal of Psychiatry
    Excerpt

    OBJECTIVE: This study sought to investigate neural activity in the amygdala during episodes of mania. METHOD: Nine manic subjects and nine healthy comparison subjects underwent functional magnetic resonance imaging (fMRI) while performing a neuropsychological paradigm known to activate the amygdala. Subjects viewed faces displaying affect (experimental task) and geometric forms (control task) and matched them to one of two simultaneously presented similar images. RESULTS: Manic subjects had significantly increased activation in the left amygdala and reduced bilateral activation in the lateral orbitofrontal cortex relative to the comparison subjects. CONCLUSIONS: Increased activation in the amygdala and decreased activation in the orbitofrontal cortex may represent disruption of a specific neuroanatomic circuit involved in mania. These brain regions may be implicated in disorders involving regulation of affect.

    Title Reduced Intracortical Myelination in Schizophrenia.
    Date August 2005
    Journal The American Journal of Psychiatry
    Title Quantifying Age-related Myelin Breakdown with Mri: Novel Therapeutic Targets for Preventing Cognitive Decline and Alzheimer's Disease.
    Date June 2005
    Journal Journal of Alzheimer's Disease : Jad
    Excerpt

    Myelin plays an essential role in brain structure and function and the human brain is uniquely dependent on the elaboration of this late invention of evolution. Our brain has the most extensive and protracted process of myelination that extends to approximately age 50 in cortical regions that have the highest risk for developing Alzheimer's disease (AD) pathology. This myelin-centered model of the human brain asserts that unique vulnerabilities of myelin, especially late-developed myelin, and the oligodendrocytes that produce it are directly pertinent to many uniquely human neuropsychiatric diseases including late-life neurodegenerative disorders such as AD. Magnetic resonance imaging (MRI) technology permits the in vivo assessment of the roughly quadratic (inverted U) lifelong trajectory of human myelin development and its subsequent breakdown. There is close agreement between neuropsychology, neuropathology, and imaging measures suggesting that the process of myelin breakdown begins in adulthood, accelerates as aging progresses, and underlies both age-related cognitive declines and the most powerful risk factor of dementia-causing disorders such as AD: age. This myelin-centered model together with the technology that makes it possible to measure the trajectory of myelin breakdown provide a framework for developing novel treatments, as well as assessing efficacy of currently available treatments, intended to slow or reverse the breakdown process in both clinically healthy as well as symptomatic populations. Such treatments can be expected to have a wide spectrum of efficacy and impact multiple human disease processes including potentially slowing brain aging and thus provide opportunities for primary prevention of age-related degenerative disorders such as AD.

    Title Adjunctive Risperidone in the Treatment of Chronic Combat-related Posttraumatic Stress Disorder.
    Date May 2005
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: The efficacy and safety of risperidone was evaluated in veteran patients with chronic combat-related posttraumatic stress disorder (PTSD) who were referred to a residential treatment program. METHODS: Seventy-three subjects volunteered to participate in this double-blind, placebo-controlled study, which comprised of a 5 week residential program followed by a 3-month outpatient follow-up. Risperidone was added to a stable psychotropic medication regimen in 92% of subjects. Primary outcome measures were the Clinician-Administered PTSD scale (CAPS-total) and its three subscales; B (Re-experiencing), C (Avoidance) and D (Arousal). Secondary outcome measures were the Hamilton Anxiety (HAM-A) and Depression (HAM-D) scales, and the Positive and Negative Syndrome Scale, Positive Subscale (PANSS-P). RESULTS: Sixty-five subjects were randomized and 48 completed the 4-month study. Significantly greater improvement in symptoms was observed in subjects receiving risperidone compared to placebo on the CAPS-total and CAPS-D subscale scores and also on HAM-A and PANSS-P. Numerically greater improvements in all the remaining measures were noted with risperidone, but the differences did not reach statistical significance. Risperidone was well tolerated. CONCLUSIONS: These results suggest that adjunctive risperidone improved a broad range of psychiatric symptoms in patients with chronic combat-related PTSD. The data support the concept that atypical antipsychotic medications may have a wider therapeutic spectrum that goes beyond the treatment of psychosis.

    Title Biological Underpinnings of Treatment Resistance in Schizophrenia: an Hypothesis.
    Date September 2004
    Journal Psychopharmacology Bulletin
    Title Heterogeneous Age-related Breakdown of White Matter Structural Integrity: Implications for Cortical "disconnection" in Aging and Alzheimer's Disease.
    Date September 2004
    Journal Neurobiology of Aging
    Excerpt

    Human and non-human primate data suggest that the structural integrity of myelin sheaths deteriorates during normal aging, especially in the late-myelinating association regions and may result in "disconnection" of widely distributed neural networks. Magnetic resonance imaging (MRI) was used to assess the heterogeneity of this process and its impact on brain aging and Alzheimer's disease (AD) by evaluating early- and later-myelinating regions of the corpus callosum, the splenium (Scc) and genu (Gcc), respectively. Calculated transverse relaxation rates (R2), an indirect measure of white matter structural integrity for the Gcc and Scc, were examined. The relationship between age and R2 differed in the two regions. A quadratic (inverted U) function with an accelerating rate of decline beginning at age 31 best represented the Gcc pattern while the Scc decline was three-fold smaller, gradual, and linear. These data suggest that the severity of age-related myelin breakdown is regionally heterogeneous, consistent with the hypothesis that differences in myelin properties make later-myelinating regions more susceptible to this process. In AD this process is globally exacerbated, consistent with an extracellular deleterious process such as amyloid beta-peptide toxicity. Non-invasive measures such as R2 may be useful in primary prevention studies of AD.

    Title Cortical Gray Matter Volumes Are Associated with Subjective Responses to Cocaine Infusion.
    Date June 2004
    Journal The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions
    Excerpt

    We analyzed the relationship between cocaine-induced euphoria and measures of frontal and temporal gray matter volumes in eleven cocaine-dependent (CD) patients who underwent magnetic resonance imaging (MRI). Self-reported ratings of the intensity of euphoric response to cocaine infusion were obtained from the CD subjects at 3, 10, and 30 minutes after cocaine infusion. Significant positive correlation between frontal and temporal cortical gray matter volume and the intensity of euphoria was observed at 10 minutes after IV cocaine. The data suggest that frontal and temporal lobe gray matter volume is associated with some of the reinforcing effects of cocaine. Given the well-established negative linear relationship between cortical gray matter volume and age, cortical gray matter volume may be a marker for the neurobiological substrate of the age-related reduction in addiction rates.

    Title Brain Ferritin Iron As a Risk Factor for Age at Onset in Neurodegenerative Diseases.
    Date May 2004
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Tissue iron can promote oxidative damage. Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Higher iron levels in males may contribute to higher risk for younger-onset PD and recent studies have linked the presence of the hemochromatosis gene with a younger age at onset of AD. We examined whether age at onset of PD and AD was associated with increased brain ferritin iron. Ferritin iron can be measured with specificity in vivo with MRI utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in three basal ganglia regions (caudate, putamen, and globus pallidus) and frontal lobe white matter for younger- and older-onset male PD and AD patients and healthy controls. Significant increases in basal ganglia FDRI levels were observed in the younger-onset groups of both diseases compared to their respective control groups, but were absent in the older-onset patients. The results support the suggestion that elevated ferritin iron and its associated toxicity is a risk factor for age at onset of neurodegenerative diseases such as AD and PD. Clinical phenomena such as gender-associated risk of developing neurodegenerative diseases and the age at onset of such diseases may be associated with brain iron levels. In vivo MRI can measure and track brain ferritin iron levels and provides an opportunity to design therapeutic interventions that target high-risk populations early in the course of illness, possibly even before symptoms appear.

    Title Differences Between Smokers and Nonsmokers in Regional Gray Matter Volumes and Densities.
    Date April 2004
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Magnetic resonance imaging (MRI) studies have demonstrated large-scale brain abnormalities in cigarette smokers, such as ventricular enlargement and atrophy. Converging lines of evidence point to functional differences between smokers and nonsmokers in specific brain regions, namely the lateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and thalamus. Using MRI, we examined these regions for differences in gray matter between smokers and nonsmokers. METHODS: Thirty-six otherwise healthy adults (19 smokers and 17 nonsmoking control subjects) underwent three-dimensional Fourier-transform spoiled-gradient-recalled acquisition MRI of the brain. Both hand-drawn regions of interest and the computer program voxel-based morphometry were used to assess group differences in regional gray matter volumes and densities, respectively. RESULTS: Smokers had smaller gray matter volumes and lower gray matter densities than nonsmokers in the PFC bilaterally, along with smaller volumes in the left dorsal ACC and lower gray matter densities in the right cerebellum. Smokers also had negative associations between pack-year smoking history and PFC gray matter densities. CONCLUSIONS: Smokers and nonsmokers differed in regional gray matter in brain areas previously linked with nicotine dependence. These findings might reflect effects of chronic smoking, predisposing traits that lead to smoking, or some combination of these factors.

    Title Age-related Myelin Breakdown: a Developmental Model of Cognitive Decline and Alzheimer's Disease.
    Date March 2004
    Journal Neurobiology of Aging
    Excerpt

    A hypothetical model of Alzheimer's disease (AD) as a uniquely human brain disorder rooted in its exceptional process of myelination is presented. Cortical regions with the most protracted development are most vulnerable to AD pathology, and this protracted development is driven by oligodendrocytes, which continue to differentiate into myelin producing cells late into the fifth decade of life. The unique metabolic demands of producing and maintaining their vast myelin sheaths and synthesizing the brain's cholesterol supply make oligodendrocytes especially susceptible to a variety of insults. Their vulnerability increases with increasing age at differentiation as later-differentiating cells myelinate increasing numbers of axonal segments. These vulnerable late-differentiating cells drive the protracted process of intracortical myelination and by increasing local cholesterol and iron levels, progressively increase the toxicity of the intracortical environment forming the basis for the age risk factor for AD. At older ages, the roughly bilaterally symmetrical continuum of oligodendrocyte vulnerability manifests as a progressive pattern of myelin breakdown that recapitulates the developmental process of myelination in reverse. The ensuing homeostatic responses to myelin breakdown further increase intracortical toxicity and results in the relentless progression and non-random anatomical distribution of AD lesions that eventually cause neuronal dysfunction and degeneration. This process causes a slowly progressive disruption of neural impulse transmission that degrades the temporal synchrony of widely distributed neural networks underlying normal brain function. The resulting network "disconnections" first impact functions that are most dependent on large-scale synchronization including higher cognitive functions and formation of new memories. Multiple genetic and environmental risk factors (e.g. amyloid beta-peptide and free radical toxicity, head trauma, anoxia, cholesterol levels, etc.) can contribute to the cognitive deficits observed in aging and AD through their impact on the life-long trajectory of myelin development and breakdown. This development-to-degeneration model is testable through imaging and post mortem methods and highlights the vital role of myelin in impulse transmission and synchronous brain function. The model offers a framework that explains the anatomical distribution and progressive course of AD pathology, some of the failures of promising therapeutic interventions, and suggests further testable hypotheses as well as novel approaches for intervention efforts.

    Title Myelination and Brain Electrophysiology in Healthy and Schizophrenic Individuals.
    Date August 2003
    Journal Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
    Title Dysregulated Brain Development in Adult Men with Schizophrenia: a Magnetic Resonance Imaging Study.
    Date May 2003
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Recent imaging evidence suggests that normal brain development/maturation of the frontal lobes and association areas is a well-regulated process consisting of continued myelination and expansion of white matter volumes into the late 40s accompanied by complementary reductions in gray matter volumes. The possibility that a dysregulation of this process may contribute to the syndrome of schizophrenia was investigated using magnetic resonance imaging. METHODS: Fifty-two normal adult males and 35 males with schizophrenia underwent magnetic resonance imaging. Coronal images were acquired using pulse sequences that maximized myelin signal. The age-related change in the gray to white matter ratio was used as a measure of developmental dysregulation in the schizophrenic subjects and contrasted to the age-related changes of the normal control group. RESULTS: Regression analyses on frontal and temporal gray to white matter ratio yielded highly significant interactions of diagnosis and age for both regions (p =.0003 and p =.01, respectively). In the normal group, both frontal and temporal gray to white matter ratios decreased significantly and linearly across the age range. In contrast, neither ratio showed meaningful age-related change in the schizophrenia group. Thus, differences in gray to white matter ratio between the groups increased markedly with age, driven primarily by the absence of a white matter volume expansion in the patient group. CONCLUSIONS: The absence of the normal complementary volume changes in the gray and white matter with age in the schizophrenic sample suggests that this dynamic developmental process is dysregulated in adult schizophrenic subjects. The importance of myelination to the continued maturation and normal functioning of the brain has implications for the diagnosis, treatment, and prognosis of schizophrenia.

    Title White Matter Structural Integrity in Healthy Aging Adults and Patients with Alzheimer Disease: a Magnetic Resonance Imaging Study.
    Date April 2003
    Journal Archives of Neurology
    Excerpt

    BACKGROUND: Imaging and postmortem studies suggest that frontal lobe white matter (FLWM) volume expands until about the age of 44.6 years and then declines. Postmortem evidence indicates that the structural integrity of myelin sheaths deteriorates during normal aging, especially in late myelinating regions such as the frontal lobes. OBJECTIVES: To assess the integrity of FLWM by magnetic resonance imaging and, thus, to provide an important index of brain aging and its relationship to Alzheimer disease (AD). DESIGN: Cross-sectional study. SETTING: Two metropolitan university hospitals and AD research centers. PARTICIPANTS: Two hundred fifty-two healthy adults (127 men and 125 women), aged 19 to 82 years, and 34 subjects with AD (16 men and 18 women), aged 59 to 85 years. MAIN OUTCOME MEASURE: Calculated transverse relaxation rate (R( 2)) of the FLWM (an indirect measure of the structural integrity of white matter). RESULTS: As expected from prior imaging data on FLWM volume, the quadratic function best represented the relationship between age and the FLWM R(2) (P<.001). In healthy individuals, the FLWM R(2) increased until the age of 38 years and then declined markedly with age. The R( 2) of subjects with AD was significantly lower than that of a group of healthy control subjects who were of similar age and sex (P<.001). CONCLUSIONS: The R(2) changes in white matter suggest that the healthy adult brain is in a constant state of change, roughly defined as periods of maturation continuing into middle age followed by progressive loss of myelin integrity. Clinically diagnosed AD is associated with more severe myelin breakdown. Noninvasive measures, such as the determination of the R(2), may have the potential to track prospectively the trajectory of deteriorating white matter integrity during normal aging and the development of AD and, thus, may be a useful marker for medication development aimed at the prevention of AD.

    Title Schizophrenia: Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation.
    Date November 2002
    Journal Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
    Excerpt

    Recent evidence suggests that the temporal extent of brain development/maturation can be expanded into middle age when maximal white matter volume and myelination are reached in frontal lobes and association areas. This temporally expanded view of brain development underlies a more comprehensive conceptual model of schizophrenia that incorporates both the reduction of gray matter volume and the complementary expansion of white matter volume occurring from adolescence until middle age. The model posits that the brain is in a constant state of well-regulated structural and functional change roughly defined as periods of development continuing into middle age followed by degeneration. Multiple genetic and environmental factors can interfere with the developmental processes resulting in a dysregulation of the complementary changes occurring in gray and white matter. This dysregulation in development results in an insufficient capacity to maintain temporal synchrony of widely distributed neural networks and is manifested in the heterogeneity of symptoms and cognitive impairments of schizophrenia. The model highlights the contributory role of myelination to synchronous brain function, provides explanations for inconsistencies in the existing literature, and suggests testable hypotheses and novel approaches for intervention efforts.

    Title Ambulatory Blood Pressure and Brain Atrophy in the Healthy Elderly.
    Date October 2002
    Journal Neurology
    Excerpt

    BACKGROUND: Brain lesions and atrophy increase with age and hypertension. OBJECTIVE: To evaluate the relationship of age and ambulatory blood pressure (BP) to brain atrophy in healthy elderly individuals. METHODS: MRI volume measurements (normalized to intracranial volume) were taken of total brain and lateral and third ventricles in 155 healthy men and women who went through extensive medical examinations. Younger (56 to 66 years old) and older (67 to 80 years old) subgroups were compared on casual and 24-hour ambulatory BP values and MRI volume measurements. RESULTS: Older subjects had smaller brain volumes and larger lateral and third ventricles. Compared with women, men had larger lateral and third ventricles. With age controlled for, greater sleep systolic BP (SBP) variability was associated with smaller brain volumes; greater waking and sleep SBP variability were associated with larger lateral and third ventricles. Subjects with higher casual and waking SBP and waking diastolic BP had larger lateral ventricles. Among older subjects, only those with elevated SBP had smaller brain volumes and larger lateral ventricles. CONCLUSIONS: These results indicate that if BP levels are within the upper normal range, even healthy individuals with no prior diagnosis of hypertension are more likely to have brain atrophy than those with lower BP. Moreover, not only do BP level and variability relate to brain atrophy, but the combination of high level and greater variability shows an even stronger relationship to brain atrophy than either one of these variables alone.

    Title Brain Maturation May Be Arrested in Chronic Cocaine Addicts.
    Date June 2002
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Animal and human newborn studies suggest that exposure to cocaine in utero delays glial maturation and white matter myelination. Postmortem data show that in the frontal and temporal lobes, white matter myelination continues into middle age. Recent magnetic resonance imaging (MRI) data have confirmed continued white matter volume increase in these regions, reaching a maximum at age 47. METHODS: Thirty-seven male cocaine dependent (CD) and 52 normal control subjects between ages 19 and 47 were evaluated with MRI. Coronal images focused on the frontal and temporal lobes were acquired using pulse sequences that maximized gray/white matter contrast. RESULTS: Highly significant positive correlations between white matter volume and age were observed in both the frontal and temporal lobes of the control group (r =.52, p =.0001 and r =.54, p =.0001, respectively); however, CD subjects did not demonstrate any age-related increase in white matter volume of the frontal (r = -.001; p =.99) and temporal (r = -.07; p =.67) lobes in this age range. CONCLUSIONS: The age-related expansion in white matter volume occurring in normal control subjects was absent in CD subjects. The findings suggest that in adults, cocaine dependence may arrest normal white matter maturation in the frontal and temporal lobes of addicts who continue using cocaine.

    Title Clinical Outcome Following Neuroleptic Discontinuation in Patients with Remitted Recent-onset Schizophrenia.
    Date December 2001
    Journal The American Journal of Psychiatry
    Excerpt

    OBJECTIVE: The goal of this report was to examine the clinical course following neuroleptic discontinuation of patients with recent-onset schizophrenia who had been receiving maintenance antipsychotic treatment for at least 1 year. METHOD: Fifty-three volunteer patients with recent-onset schizophrenia who had been clinically stabilized on a maintenance regimen of fluphenazine decanoate for a mean of 16.7 months had their antipsychotic medications withdrawn under clinical supervision. Participants initially entered a 24-week, double-blind crossover trial in which fluphenazine and placebo were administered for 12 weeks each. For those who did not experience symptom exacerbation or relapse during this period, fluphenazine was openly withdrawn; participants were then followed for up to 18 additional months. RESULTS: When a low threshold for defining symptom reemergence was used, 78% (N=39 of 50) of the patients experienced an exacerbation or relapse within 1 year; 96% (N=48 of 50) did so within 2 years. Mean time to exacerbation or relapse was 235 days. When hospitalization was used as a relapse criterion, only six of 45 of individuals (13%) experiencing an exacerbation or relapse who continued in treatment in the clinic were hospitalized, demonstrating the sensitivity of the psychotic exacerbation criterion. CONCLUSIONS: The vast majority of clinically stable individuals with recent-onset schizophrenia will experience an exacerbation or relapse after antipsychotic discontinuation, even after more than a year of maintenance medication. However, clinical monitoring and a low threshold for reinstating medications can prevent hospitalization for the majority of these patients.

    Title Age-related Changes in Frontal and Temporal Lobe Volumes in Men: a Magnetic Resonance Imaging Study.
    Date May 2001
    Journal Archives of General Psychiatry
    Excerpt

    BACKGROUND: Imaging and postmortem studies provide converging evidence that, beginning in adolescence, gray matter volume declines linearly until old age, while cerebrospinal fluid volumes are stable in adulthood (age 20-50 years). Given the fixed volume of the cranium in adulthood, it is surprising that most studies observe no white matter volume expansion after approximately age 20 years. We examined the effects of the aging process on the frontal and temporal lobes. METHODS: Seventy healthy adult men aged 19 to 76 years underwent magnetic resonance imaging. Coronal images focused on the frontal and temporal lobes were acquired using pulse sequences that maximized gray vs white matter contrast. The volumes of total frontal and temporal lobes as well as the gray and white matter subcomponents were evaluated. RESULTS: Age-related linear loss in gray matter volume in both frontal (r = -0.62, P<.001) and temporal (r = -0.48, P<.001) lobes was confirmed. However, the quadratic function best represented the relationship between age and white matter volume in the frontal (P<.001) and temporal (P<.001) lobes. Secondary analyses indicated that white matter volume increased until age 44 years for the frontal lobes and age 47 years for the temporal lobes and then declined. CONCLUSIONS: The changes in white matter suggest that the adult brain is in a constant state of change roughly defined as periods of maturation continuing into the fifth decade of life followed by degeneration. Pathological states that interfere with such maturational processes could result in neurodevelopmental arrests in adulthood.

    Title Fluphenazine Levels During Maintenance Treatment of Recent-onset Schizophrenia: Relation to Side Effects, Psychosocial Function and Depression.
    Date December 2000
    Journal Psychopharmacology
    Excerpt

    RATIONALE: The utility of fluphenazine levels during maintenance treatment of schizophrenia is still unclear. OBJECTIVES: This study investigated the relationship between fluphenazine levels and a variety of clinical measures during maintenance treatment of schizophrenia. METHODS: Fluphenazine levels, side effects, depression and psychosocial outcome were measured at five time points over approximately 1 year in 59 recent onset schizophrenic patients treated with a maintenance dose of injectable fluphenazine decanoate. Negative symptoms were evaluated at the 1-year endpoint. RESULTS: Fluphenazine levels showed marked intraindividual variability even when measurements were restricted to the second 6 months of treatment, by which time steady state levels should have been achieved. No consistent relationship was found between fluphenazine levels and any of the outcome measures. CONCLUSIONS: The results of this study suggest that fluphenazine plasma levels do not routinely add relevant clinical information beyond that of dose in evaluating potential side effects or negative consequences during maintenance treatment with the decanoate form of the medication.

    Title Increased Csf Volumes Are Associated with Diminished Subjective Responses to Cocaine Infusion.
    Date October 2000
    Journal Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
    Excerpt

    We evaluated the hypothesis that ventricular and cortical CSF volume increases are associated with reductions in the magnitude of euphoric effects produced by intravenous IV cocaine infusion in cocaine dependent (CD) individuals. Eleven CD patients participating in a cocaine-infusion study and eleven control subjects underwent magnetic resonance imaging (MRI). Two CSF regions of interest (lateral ventricles and frontal cortex CSF) and two comparison regions (third ventricle and posterior cortex CSF) were measured. Self-reported ratings of the intensity of euphoric response ("high") were obtained from the CD subjects at 3, 10, and 30 minutes after IV administration of cocaine. A significant negative correlation was observed between the volume of the lateral ventricles and subjective ratings of the "high" experienced at 3 minutes, but not at 10 and 30 minutes after cocaine infusion. In contrast, a significant negative correlation between frontal cortex CSF volume and the intensity of euphoric response was observed at 30 minutes after IV cocaine. No significant associations were observed between the volumes of the two comparison regions and any subjective ratings of "high." No significant volume differences were observed between the CD and control groups in any region. The results suggest larger lateral ventricular volumes are associated with a decrease in immediate euphoria while larger frontal cortex CSF volumes are associated with a decrease in the duration of the euphoria induced by cocaine infusion. The age-related brain volume reductions underlying the volume increase in these two CSF spaces may be the neurobiological basis of the age-related reduction in the rates of addiction.

    Title Mri Evaluation of Basal Ganglia Ferritin Iron and Neurotoxicity in Alzheimer's and Huntingon's Disease.
    Date October 2000
    Journal Cellular and Molecular Biology (noisy-le-grand, France)
    Excerpt

    BACKGROUND: The basal ganglia contain the highest levels of iron in the brain and post-mortem studies indicate a disruption of iron metabolism in the basal ganglia of patients with neurodegenerative disorders such as Alzheimer's disease (AD) and Huntington's disease (HD). Iron can catalyze free radical reactions and may contribute to oxidative damage observed in AD and HD brain. Magnetic resonance imaging (MRI) can quantify transverse relaxation rates, which can be used to quantify tissue iron stores as well as evaluate increases in MR-visible water (an indicator of tissue damage). METHODS: A magnetic resonance imaging (MRI) method termed the field dependent relaxation rate increase (FDRI) was employed which quantifies the iron content of ferritin molecules (ferritin iron) with specificity through the combined use of high and low field-strength MRI instruments. Three basal ganglia structures (caudate, putamen and globus pallidus) and one comparison region (frontal lobe white matter) were evaluated. Thirty-one patients with AD and a group of 68 older control subjects, and 11 patients with HD and a group of 27 adult controls participated (4 subjects overlap between AD and HD controls). RESULTS: Compared to their respective normal control groups, increases in basal ganglia FDRI levels were seen in both AD and HD. FDRI levels were significantly increased in the caudate (p = 0.007) and putamen (p = 0.008) of patients with AD with a trend toward an increase in the globus pallidus (p = 0.13). In the patients with HD, all three basal ganglia regions showed highly significant FDRI increases (p<0.001) and the magnitude of the increases were 2 to 3 times larger than those observed in AD versus control group comparison. For both HD andAD subjects, the basal ganglia FDRI increase was not a generalized phenomenon, as frontal lobe white matter FDRI levels were decreased in HD (p = 0.015) and remained unchanged in AD. Significant low field relaxation rate decreases (suggestive of increased MR-visible water and indicative of tissue damage) were seen in the frontal lobe white matter of both HD and AD but only the HD basal ganglia showed such decreases. CONCLUSIONS: The data suggest that basal ganglia ferritin iron is increased in HD and AD. Furthermore, the increased iron levels do not appear to be a byproduct of the illness itself since they seem to be present at the onset of the diseases, and thus may be considered a putative risk factor. Published post-mortem studies suggest that the increase in basal ganglia ferritin iron may occur through different mechanisms in HD and AD. Consistent with the known severe basal ganglia damage, only HD basal ganglia demonstrated significant decreases in low field relaxation rates. MRI can be used to dissect differences in tissue characteristics, such as ferritin iron and MR-visible water, and thus could help clarify neuropathologic processes in vivo. Interventions aimed at decreasing brain iron levels, as well as reducing the oxidative stress associated with increased iron levels, may offer novel ways to delay the rate of progression and possibly defer the onset of AD and HD.

    Title An Mri Study of Temporal Lobe Structures in Men with Bipolar Disorder or Schizophrenia.
    Date September 2000
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia. The specificity of this finding to schizophrenia remains to be determined. The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated. METHODS: Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging. Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups. Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained. RESULTS: Hippocampal volumes were significantly smaller in the schizophrenic group than in both bipolar and normal comparison subjects. Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects. CONCLUSIONS: The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders.

    Title Age-related Brain Volume Reductions in Amphetamine and Cocaine Addicts and Normal Controls: Implications for Addiction Research.
    Date July 2000
    Journal Psychiatry Research
    Excerpt

    The study evaluated the relationship between age and frontal and temporal lobe volumes in young cohorts of cocaine-dependent (CD), amphetamine-dependent (Am), and normal control subjects. Ten CD, nine Am, and 16 age- and gender-matched control subjects underwent magnetic resonance imaging (MRI). The volume of the frontal and temporal lobes was measured from an identically positioned slab of seven contiguous 3-mm-thick coronal images. Follow-up measures of the gray and white matter subcomponents of these volumes were also obtained. Both CD and Am groups had a significantly smaller temporal lobe volumes, but only the CD group demonstrated a significantly greater decline in temporal lobe volume with age (intracranial volume, education, and race were controlled for in all statistical analyses). Segmenting the brain regions into gray and white matter revealed that the negative correlation between age and temporal lobe volume of CD patients was mostly due to a significant age-related decline in the gray matter subcomponent. Negative trends between age and gray matter volumes were also observed in the Am and normal groups. In the frontal lobes, age was negatively correlated with gray matter volume in the control, CD, and Am groups. Unlike the consistent decreases in gray matter volumes, white matter showed non-significant increases in volume with age. The data suggest that CD patients may have an accelerated age-related decline in temporal lobe gray matter volume and a smaller temporal lobe volume compared to normal controls. In the frontal lobe, age-related gray matter volume reductions occur in all three groups. These age-related cortical gray matter volume reductions may be a biological marker for the risk of addictive behavior, which also decreases with age.

    Title Abstinence from Cocaine Reduces High-risk Responses on a Gambling Task.
    Date January 2000
    Journal Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
    Title In Vivo Evaluation of Brain Iron in Alzheimer Disease Using Magnetic Resonance Imaging.
    Date January 2000
    Journal Archives of General Psychiatry
    Excerpt

    BACKGROUND: The basal ganglia contain the highest levels of iron in the brain, and postmortem studies indicate a disruption of iron metabolism in the basal ganglia of patients with Alzheimer disease (AD). Iron can catalyze free radical reactions and may contribute to oxidative damage observed in AD brains. Treatments aimed at reducing oxidative damage have offered novel ways to delay the rate of progression and could possibly defer the onset of AD. Brain iron levels were quantified in vivo using a new magnetic resonance imaging method. METHODS: Thirty-one patients with AD and 68 control subjects participated in this study. A magnetic resonance imaging method was employed that quantifies the iron content of ferritin molecules (ferritin iron) with specificity through the combined use of high and low field-strength magnetic resonance imaging instruments. Three basal ganglia structures (caudate, putamen, and globus pallidus) and one comparison region (frontal lobe white matter) were evaluated. RESULTS: Basal ganglia ferritin iron levels were significantly increased in the caudate (P = .007; effect size, 0.69) and putamen (P = .008; effect size, 0.67) of AD subjects, with a trend toward an increase in the globus pallidus (P = .13). The increased basal ganglia ferritin iron levels were not a generalized phenomenon; white matter ferritin iron levels were unchanged in patients with AD (P = .50). CONCLUSIONS: The data replicate and extend prior results and suggest that basal ganglia ferritin iron levels are increased in AD. Prospective studies are needed to evaluate whether premorbid iron levels are increased in individuals who develop AD.

    Title Magnetic Resonance Imaging Evidence of "silent" Cerebrovascular Toxicity in Cocaine Dependence.
    Date January 2000
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Cocaine and its metabolites can produce vasospasm. Cocaine-dependent (CD) patients are at increased risk for stroke, and a high frequency of brain perfusion defects has been observed in clinically asymptomatic CD subjects. This is the first controlled magnetic resonance imaging (MRI) study of clinically asymptomatic CD subjects. METHODS: Two age-matched groups of male subjects (61 CD and 57 control) participated in the study. Subjects with a history of neurologic symptoms or major medical or neurologic illness, such as hypertension, diabetes, or significant head trauma, were excluded. The severity of hyperintense lesions observed on T2-weighted MRI images were rated on a 0-3-point scale by an experienced radiologist who was blind to all clinical data. Ratings of 3 were felt to be significant indicators of a possible disease process and were used in the data analysis. Three regions were separately rated: the cerebral white matter, subinsular white matter, and subcortical gray matter (basal ganglia and thalamus region). RESULTS: Despite the exclusion criteria minimizing risk factors for cerebrovascular events, 17 of the 61 (27.9%) CD subjects and 4 of 57 (7%) of the control subjects had severe hyperintense lesions suggestive of subclinical or "silent" anoxic vascular events. Significant group differences were observed in the two white matter regions but not in the subcortical gray matter region. The risk of severe white matter lesions in the CD group increased with age, reaching 50% in the oldest age quartile (46-58 years), and this increase was not related to the number of years cocaine was used. CONCLUSIONS: The data suggest that asymptomatic CD patients are a heterogeneous population with a significantly increased age-related risk of white matter neurovascular toxicity. Premature neurovascular damage may impact treatment outcomes and, as the CD population ages, may manifest as an increased incidence of cognitive deficits.

    Title Choreoathetoid Movements in Cocaine Dependence.
    Date December 1999
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: To evaluate the severity of choreoathetoid movements in cocaine dependent (CD) subjects and age-matched normal control subjects. METHODS: Choreoathetoid movements were evaluated using the Abnormal Involuntary Movement Scale (AIMS) in samples of 71 CD, 56 normal control, and 9 amphetamine-dependent male subjects. RESULTS: The CD subjects had a significantly increased nonfacial (limbs plus body) AIMS subscore. When the nonfacial AIMS scores of the two groups were compared in relation to age, a significant age by diagnosis interaction was observed, indicating that the differences between groups were most marked in the younger age groups. The facial AIMS scores were also increased but only in the youngest CD cohort (under 32 years of age). The comparison group of 9 younger amphetamine-dependent subjects also showed increased AIMS scores. CONCLUSIONS: Increases in choreoathetoid movements in younger cocaine and amphetamine-dependent subjects may be related to their psychostimulant use. The absence of differences in choreoathetoid movements between the older CD subjects and normal control subjects may represent an age-related self-selection effect.

    Title The Incidence of T2-weighted Mr Imaging Signal Abnormalities in the Brain of Cocaine-dependent Patients is Age-related and Region-specific.
    Date December 1999
    Journal Ajnr. American Journal of Neuroradiology
    Excerpt

    BACKGROUND AND PURPOSE: Cocaine and its metabolites can produce vasospasm, and cocaine-dependent patients are at increased risk for stroke. Based on previous case reports, we hypothesized that the incidence of hyperintense brain lesions observed on T2-weighted MR images would also be increased in asymptomatic cocaine-dependent individuals. METHODS: Sixty-two male "crack" (smoked) cocaine-dependent participants ranging in age from 25 to 66 years were compared with 116 normal male control participants ranging in age from 25 to 80 years. Those with histories of neurologic symptoms or illnesses were excluded. The severity of hyperintense lesions was rated on a 0- to 3-point scale, and ratings of 3 were used in the data analysis as an indicator of a probable pathologic process. Three regions were separately rated: the cerebral white matter, insular subcortex white matter, and subcortical gray matter (basal ganglia and thalamus region). RESULTS: Significantly increased risk of severe lesions was observed in the two white matter regions of the cocaine-dependent group (odds ratio of 16.7 and 20.3) but not in the subcortial gray matter region (odds ratio of 1.4). In the insula subcortex white matter, the risk of lesions increased with age in the cocaine-dependant sample, but remained essentially absent among normal controls through the age of 80 years. In the cerebral white matter, the relationship of age and risk of lesion among normal participants was similar in shape to that in cocaine-dependent participants, but equivalent risk was seen 20 years earlier among cocaine-dependent participants. CONCLUSIONS: Cocaine-dependent participants had a significantly increased age-related risk of white matter damage. The possible clinical implications of this damage are discussed.

    Title Selegiline Effects on Cocaine-induced Changes in Medial Temporal Lobe Metabolism and Subjective Ratings of Euphoria.
    Date June 1999
    Journal Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
    Excerpt

    To test the effect of selegiline, a specific monoamine oxidase B (MAO-B) inhibitor, on the cerebral metabolic and euphorigenic effects of cocaine in experienced users, eight cocaine-dependent (CD) subjects were evaluated using a within-subjects design. Each subject participated in two pairs of [F-18]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans (baseline scan followed 24 h later by a second scan obtained in conjunction with a 40-mg cocaine infusion) performed before and after a 1-week period of daily treatment with 10 mg selegiline administered orally. The hippocampus and amygdala were evaluated because of their hypothesized involvement in the addiction process, and the thalamus was evaluated as a comparison region. Following 7 days of selegiline treatment, the magnitude of the subjective euphoria ("high") produced by cocaine infusion was reduced by 40% (cocaine by selegiline interaction F = 7.15, df = 1.21, p = .014). Selegiline treatment also altered glucose utilization (normalized against whole brain counts) in the two limbic regions, but not the thalamus. In the amygdala, the effects of cocaine differed, depending upon whether or not patients were being treated with selegiline (cocaine by selegiline interaction F = 4.67, df = 1,19.8, p = .043). A different effect was observed in the hippocampus, where selegiline treatment decreased metabolic activity irrespective of whether cocaine was given (main effect F = 7.70, df = 1.20, p = .012). The concomitant changes in both the subjective experience of the "high" and normalized amygdala glucose utilization after selegiline treatment, suggest that a relationship exists between cocaine-induced euphoria and limbic metabolism. The data suggest that selegiline may be a useful adjunct in the treatment of cocaine dependence.

    Title Increased Basal Ganglia Iron Levels in Huntington Disease.
    Date May 1999
    Journal Archives of Neurology
    Excerpt

    OBJECTIVE: To quantify in vivo brain ferritin iron levels in patients with Huntington disease (HD) and normal control subjects. DESIGN AND SUBJECTS: A magnetic resonance imaging method that can quantify ferritin iron levels with specificity in vivo was employed to study 11 patients with HD and a matched group of 27 normal controls. Three basal ganglia structures (caudate, putamen, and globus pallidus) and 1 comparison region (frontal lobe white matter) were evaluated. RESULTS: Basal ganglia iron levels were significantly increased (P<.002) in patients with HD, and this increase occurred early in the disease process. This was not a generalized phenomenon, as white matter iron levels were lower in patients with HD. CONCLUSIONS: The data suggest that increased iron levels may be related to the pattern of neurotoxicity observed in HD. Reducing the oxidative stress associated with increased iron levels may offer novel ways to delay the rate of progression and possibly defer the onset of HD.

    Title Mri Evaluation of Brain Iron in Earlier- and Later-onset Parkinson's Disease and Normal Subjects.
    Date April 1999
    Journal Magnetic Resonance Imaging
    Excerpt

    Tissue iron levels in the extrapyramidal system of earlier- and later-onset Parkinson's disease (PD) subjects were evaluated in vivo using a magnetic resonance imaging (MRI) method. The method involves scanning subjects in both high- and low-field MRI instruments, measuring tissue relaxation rate (R2), and calculating the field-dependent R2 increase (FDRI) which is the difference between the R2 measured with the two MRI instruments. In tissue, only ferritin iron is known to increase R2 in a field-dependent manner and the FDRI measure is a specific measure of this tissue iron pool. Two groups of male subjects with PD and two age-matched groups of normal control males were studied. The two groups of six subjects with PD consisted of subjects with earlier- or later-onset (before or after age 60) PD. FDRI was measured in five subcortical structures: the substantia nigra reticulata (SNR), substantia nigra compacta (SNC), globus pallidus, putamen, and caudate nucleus, and in one comparison region; the frontal white matter. Earlier-onset PD subjects had significant (p < 0.05) increases in FDRI in the SNR, SNC, putamen, and globus pallidus, while later-onset PD subjects had significantly decreased FDRI in the SNR when compared to their respective age-matched controls. Controlling for illness duration or structure size did not meaningfully alter the results. Published post-mortem studies on SN iron levels indicate decreased ferritin levels and increased free iron levels in the SN of older PD subjects, consistent with the decreased FDRI observed in our later-onset PD sample, which was closely matched in age to the post-mortem PD samples. The FDRI results suggest that disregulation of iron metabolism occurs in PD and that this disregulation may differ in earlier- versus later-onset PD.

    Title Tardive Dyskinesia and Serum Iron Indices.
    Date December 1998
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: This study was undertaken to evaluate whether peripheral (serum) markers of iron status are associated with severity of the choreoathetoid movements seen in tardive dyskinesia (TD). METHODS: Serum iron indices (ferritin, iron, and total iron binding capacity) and fluphenazine levels were measured in a group of 30 male DSM-III diagnosed schizophrenic patients chronically treated with fluphenazine decanoate. The severity of choreoathetoid movements was assessed with the Abnormal Involuntary Movement Scale (AIMS), and akathisia was assessed with the Barnes scale. RESULTS: A significant positive correlation was observed between AIMS scores and serum ferritin. This relationship remained significant after controlling for age and plasma fluphenazine levels. No significant correlations were observed between serum iron or total iron binding capacity and choreoathetoid movement ratings. There were no significant associations between serum iron indices and akathisia ratings. CONCLUSIONS: The data suggest that choreoathetoid movements are associated with serum ferritin levels in chronically medicated male schizophrenic patients. This relationship does not seem to be caused by an association of these variable with age or plasma fluphenazine levels. In addition, the relationship seems to be specific, since other iron indices and another extrapyramidal side effect (akathisia) do not demonstrate a similar relationship. In view of reports that antipsychotic medications change normal iron metabolism and increase iron uptake into the brain, the current results could be interpreted to suggest that serum ferritin levels may be a risk factor for TD in patients treated with "classic" antipsychotic medications.

    Title Reliability of Medial Temporal Lobe Volume Measurements Using Reformatted 3d Images.
    Date September 1998
    Journal Psychiatry Research
    Excerpt

    The study assessed whether standardizing the angle of image display and controlling for head position in three planes affects the scan-rescan reliability of medial temporal lobe volume measures when very thin (1.5 mm) slices are used. Five volunteers were scanned two times on consecutive days. A three-dimensional MRI sequence acquired whole brain data in 1.4 mm thick coronal slices. The data were displayed as 1.5 mm thick images and were rated both in the originally acquired coronal plane, and after reformatting to correct for head tilt and display the brain in the coronal plane perpendicular to the long axis of the left anterior hippocampus. One rater measured five brain regions (temporal lobe, anterior and posterior hippocampus, amygdala, and temporal horn) on the left and right sides of the two non-reformatted and two reformatted scans to obtain inter-scan variance. Furthermore, most scans were remeasured, to obtain 'reread' variances. All data were log-transformed in order to produce comparable variability across brain regions of different sizes. For all the regions, except the temporal horn, the non-reformatted scans showed significantly larger scan-rescan variability than the reformatted scans. A typical standard deviation for a non-reformatted pair of scans was 0.10, corresponding to 26% error, while a typical value for a reformatted pair of scans was 0.04, corresponding to 10% error. For all the regions, the reread data (intra-rater reliability) gave similar results for both reformatted and non-reformatted images with similar standard deviations (typical value for reread standard deviation was 0.020, corresponding to 5% error). The data suggest that, even when very thin slices are acquired, volume measurement accuracy of gray matter structures in the temporal lobe is considerably improved by controlling for image orientation in three planes. For these structures, the sample size needed to detect a small (5%) within-subject volume change would be halved if reformatted images were used. Image contrast is an additional important factor since the reformatted T1 weighted images used in this study, which have suboptimal CSF/brain contrast, worsened measurement accuracy in the temporal horn.

    Title Amygdala Enlargement in Bipolar Disorder and Hippocampal Reduction in Schizophrenia: an Mri Study Demonstrating Neuroanatomic Specificity.
    Date July 1998
    Journal Archives of General Psychiatry
    Title Relationship Between Blood Pressure and Subcortical Lesions in Healthy Elderly People.
    Date April 1998
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: The relationship between blood pressure (BP) and heart rate (HR) and MRI assessments of subcortical T2 hyperintensities was evaluated in healthy elderly men and women. METHODS: Casual and 24-hour ambulatory BPs and HR measurements were taken of 144 elderly individuals, aged 55 to 79 years. Subjects had no evidence of previous health disorders. MRI scans of white matter, subcortical gray matter, and insular subcortex were coded for severity of hyperintensities. RESULTS: Mean casual BP for the group was 120/72 mm Hg. With age and sex accounted for, individuals with the highest severity rating of white matter hyperintensities had higher casual, awake, and sleep systolic BPs; higher awake diastolic BPs; greater awake systolic BP variability; and a smaller nocturnal fall in systolic and diastolic BPs than individuals with less severe ratings. Higher severity ratings for subcortical gray matter hyperintensities were associated with elevations in casual, awake, and asleep systolic BPs and a smaller HR drop during sleep. Subjects with higher ratings for the insular subcortex had higher systolic and diastolic BPs (casual, awake, and asleep), greater HR variability during sleep, and a smaller nocturnal fall in HR. CONCLUSIONS: Casual and 24-hour ambulatory BPs and some ambulatory HR measures are associated with subcortical lesions of the brain. Longitudinal studies are needed to further explore the relationship between white matter lesions and cardiovascular measures, as well as the significance of these lesions for cerebrovascular disease in healthy elderly subjects.

    Title Mr Evaluation of Age-related Increase of Brain Iron in Young Adult and Older Normal Males.
    Date June 1997
    Journal Magnetic Resonance Imaging
    Excerpt

    The purposes of this study were to extend the investigation of age-related increases in brain iron to a younger age group, replicate previously published results, and further evaluate the validity of a novel noninvasive magnetic resonance (MR) method for measuring tissue iron (ferritin) levels with specificity. The method consists of measuring the dependence of tissue transverse relaxation rates (R2) on the field strength of MR instruments. Two MR instruments operating at 1.5 and 0.5 T were used to measure the field-dependent R2 increase (FDRI) in the frontal white matter, caudate, putamen, and globus pallidus. A group of 13 normal adult males (ages 21-77), with seven subjects below and six above age 35, was examined. As expected from postmortem and prior FDRI data, robust and significant age-related increases in FDRI were observed in the caudate, putamen, and globus pallidus, with the globus pallidus FDRI increasing sharply in the second decade and reaching a plateau after age 30. In addition, we replicated previous reports showing very high correlations between FDRI and published brain iron levels for the four regions examined. The data replicate and extend previous FDRI observations on brain aging and are consistent with postmortem data on age-related increases in brain iron. These results are relevant to the investigation of age-related neurodegenerative diseases in which iron may catalyze toxic free radical reactions.

    Title Age at Illness Onset and Left Temporal Lobe Length in Males with Schizophrenia.
    Date February 1997
    Journal Psychiatry Research
    Excerpt

    Post-mortem data suggest that in schizophrenia, temporal lobe length may be associated with age at illness onset. We used sagittal magnetic resonance images standardly acquired in reference to a coronal pilot image to obtain linear measurements of the left hemisphere in 38 male schizophrenic patients early in the course of their illness and 21 matched normal controls. In addition to temporal lobe and anterior temporal lobe (anterior to the anterior commissure) lengths, measurements of maximal brain and skull lengths were also obtained. The data show that differences in temporal lobe length between patients and normal controls are primarily due to significant differences between the groups in the global measures of brain and skull lengths. However, within the patient group, a significant association between temporal lobe length and age at onset of psychosis was observed. The same association was observed when the anterior part of the temporal lobe was measured separately. These associations remained significant after controlling for multiple variables such as subject height and brain and skull lengths. Further statistical evaluations showed that the temporal lobe was significantly shorter among the subgroup of schizophrenics whose illness began before the age of 23. The data suggest that temporal lobe length may be a useful variable for investigating the biological heterogeneity of schizophrenia and highlight important technical issues regarding current efforts to measure the volumes of temporal lobe structures.

    Title Clinical and Mri Evaluation of Psychostimulant Neurotoxicity.
    Date December 1996
    Journal Nida Research Monograph
    Title Positron-emission Tomography in Tardive Dyskinesia.
    Date February 1996
    Journal The Journal of Neuropsychiatry and Clinical Neurosciences
    Excerpt

    Cerebral glucose metabolic rates were determined in normal control subjects (n = 26) and schizophrenic patients with tardive dyskinesia (n = 14). Globus pallidus and primary motor cortex (precentral gyrus) metabolic values divided by those of the cerebral hemispheres were significantly increased in the patient group. A similar metabolic pattern has not been reported for schizophrenic patients without tardive dyskinesia, and the abnormalities were demonstrated despite the normal appearance of the basal ganglia on X-ray CT. The findings differed markedly from the reduced metabolic rates of the basal ganglia previously identified in other choreiform disorders, including Huntington's and Wilson's diseases. The findings suggest that tardive dyskinesia is characterized by increased pallidal synaptic activity resulting from either altered striatopallidal input or increased pallidal interneuron firing.

    Title Magnetic Resonance Imaging Evaluation of Brain Iron Levels.
    Date November 1995
    Journal Biological Psychiatry
    Title The Vulnerability/stress Model of Schizophrenic Relapse: a Longitudinal Study.
    Date October 1994
    Journal Acta Psychiatrica Scandinavica. Supplementum
    Excerpt

    A tentative model for conceptualizing the interplay of vulnerability factors, stressors, and protective factors in the course of schizophrenia is discussed. A study of the initial years after a first schizophrenic episode is testing the predictive role of key factors. During an initial 1-year period of depot antipsychotic medication, independent life events and expressed emotion were found to predict the likelihood of psychotic relapse. Initial analyses indicate that independent life events play less of a role in relapse prediction during a medication-free period. These results suggest that maintenance antipsychotic medication raises the threshold for return of psychotic symptoms, such that relapses are less likely unless major environmental stressors occur. A low expressed emotion environment may be a protective factor.

    Title In Vivo Mr Evaluation of Age-related Increases in Brain Iron.
    Date September 1994
    Journal Ajnr. American Journal of Neuroradiology
    Excerpt

    PURPOSE: To assess the validity of an MR method of evaluating tissue iron. METHODS: The difference between the transverse relaxation rate (R2) measured with a high-field MR instrument and the R2 measured with a lower field instrument defines a measure termed the field-dependent R2 increase (FDRI). Previous in vivo and in vitro studies indicated that FDRI is a specific measure of tissue iron stores (ferritin). T2 relaxation times were obtained using two clinical MR instruments operating at 0.5 T and 1.5 T. T2 relaxation times were measured in the frontal white matter, caudate nucleus, putamen, and globus pallidus of 20 healthy adult male volunteers with an age range of 20 to 81 years. R2 was calculated as the reciprocal of T2 relaxation time. These in vivo MR results were correlated with previously published postmortem data on age-related increases of nonheme iron levels. RESULTS: The FDRI was very highly correlated with published brain iron levels for the four regions examined. In the age range examined, robust and highly significant age-related increases in FDRI were observed in the caudate and putamen. The correlations of age and FDRI in the globus pallidus and white matter were significantly lower and did not have statistical significance. CONCLUSIONS: The data provide additional evidence that FDRI is a specific measure of tissue iron stores. The data also show that age-related increases in tissue iron stores can be quantified in vivo despite significant age-related processes that oppose the increase in R2 caused by iron. These results are relevant to the investigation of neurodegenerative processes in which iron may catalyze toxic free-radical reactions.

    Title In Vivo Evaluation of Brain Iron in Alzheimer's Disease and Normal Subjects Using Mri.
    Date August 1994
    Journal Biological Psychiatry
    Excerpt

    Magnetic resonance imaging (MRI) can measure transverse relaxation rate (R2) of tissues. Although R2 is increased by tissue iron levels, R2 is not a specific measure of iron. A new method, based on the fact that ferritin (the primary tissue iron storage protein) affects R2 in a field-dependent manner, can quantify tissue iron with specificity by measuring the Field Dependent R2 Increase (FDRI). Using the FDRI method, we compared brain iron stores in frontal white matter, caudate nucleus, putamen, and globus pallidus of five male patients with Alzheimer disease (AD) and eight age and gender-matched normal controls. FDRI values were significantly higher among AD patients in the caudate and globus pallidus. The data suggest that AD may involve disturbances in brain iron metabolism and that the involvement of iron in the pathophysiology of age-related neurodegenerative disorders can be investigated in vivo using MRI.

    Title Reliability of in Vivo Volume Measures of Hippocampus and Other Brain Structures Using Mri.
    Date December 1993
    Journal Magnetic Resonance Imaging
    Excerpt

    Volume reductions of the hippocampus are associated with Alzheimer's disease, schizophrenia, and epilepsy. We used clinically available MRI methods (2D acquisition; inversion recovery and calculated T2 images; 3 mm contiguous slices) that optimize image contrast, quality, and resolution and standardized positioning protocols to maximize the in vivo accuracy (test-retest reliability) of brain volume measurements in volunteers who were scanned two or three times. Volunteers were scanned in the same MRI instrument (intrascanner reliability) as well as in two different instruments (interscanner reliability). A single rater obtained brain volume measures of seven contiguous slices centered on the anterior commissure. The in vivo intrascanner reliability for measures of anterior hippocampus and ventricular volumes was very good, with reliability coefficients [intraclass r (rxx)] ranging between .855 and .997, and a median coefficient of variation (CV) of 6.4%. Reliability was good for amygdala (rxx of .740 and .764) and for total frontal and temporal lobe volumes and white matter volume measures (rxx ranging between .640 and .823, median coefficient of variation was 3.2%). Overall, interscanner reliability was also good. We discuss the implications of our results relative to the possible clinical utility of hippocampal quantification and the feasibility of prospective studies aimed at quantifying progressive neurodegeneration.

    Title Preliminary Associations Between Motor Procedural Learning, Basal Ganglia T2 Relaxation Times, and Tardive Dyskinesia in Schizophrenia.
    Date July 1993
    Journal Psychiatry Research
    Excerpt

    The hypothesis that the caudate nucleus is involved in the pathophysiology of tardive dyskinesia (TD) in schizophrenia was investigated by examining motor procedural learning on the pursuit rotor task and basal ganglia T2 relaxation times (T2) determined using magnetic resonance imaging (MRI). Increased severity of TD was associated with shortened caudate T2 and decreased motor learning. Motor-learning scores of schizophrenic patients with and without TD did not differ significantly from those of normal control subjects, but motor learning in the schizophrenic patients correlated with caudate T2. The results suggest that a corticocaudate system subserves motor procedural learning and provide converging evidence from neuropsychological and MRI measures suggesting caudate involvement in TD.

    Title Field Dependent Transverse Relaxation Rate Increase May Be a Specific Measure of Tissue Iron Stores.
    Date May 1993
    Journal Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
    Excerpt

    The degree to which MRI magnet field strength affects measured transverse relaxation rates (R2) defines a measure termed the field dependent R2 increase (FDRI). We report here the results of in vivo and in vitro experiments that were conducted to evaluate whether FDRI is a potentially useful measure of tissue iron stores. T2 relaxation times were obtained using two clinical MRI instruments operating at 0.5 and 1.5 Tesla, and relaxation rates (R2) were calculated as the reciprocal of T2. The in vivo experiment measured R2 in human brain frontal white matter, caudate nucleus, putamen, and globus pallidus. The FDRI was very highly correlated with published brain iron levels for the four regions examined. The in vitro experiment measured R2 in agarose gel-based phantoms containing physiologic forms and amounts proteins involved in iron storage and transport (ferritin, apoferritin, transferrin, and apotransferrin). Significant field dependence was observed only for the ferritin phantoms. The differences in the R2 values obtained at the two field strengths were striking, and were proportional to the ferritin levels of the phantoms. These studies suggest that FDRI may be a specific measure of tissue ferritin. The quantitative significance of the results to imaging and possible applications to the clinical investigation of pathologic states are discussed.

    Title T2 Hyperintense Foci on Magnetic Resonance Images of Schizophrenic Patients and Controls.
    Date June 1992
    Journal Psychiatry Research
    Excerpt

    High resolution magnetic resonance imaging (MRI) of the brain was performed on 18 male schizophrenic patients and 15 male normal control subjects using an identical imaging protocol. The number and size of T2 hyperintense foci were clinically quantified by an academic radiologist. Large foci (greater than or equal to 3 mm in diameter) were observed more frequently on patient images (7/18) than on control images (1/15). The imaging protocol detected high rates of focal hyperintensities, but no differences between patients and controls were noted in the total affected brain area (sum of focal areas) or in the presence or absence of foci.

    Title Mri in Tardive Dyskinesia: Shortened Left Caudate T2.
    Date April 1991
    Journal Biological Psychiatry
    Excerpt

    High-resolution magnetic resonance imaging of the brain was performed on 18 male schizophrenic patients, 14 with a cumulative exposure to neuroleptics of more than 1 year and 4 with less than 3 months of exposure. Calculated T2 relaxation time values were obtained for the basal ganglia. Patients with tardive dyskinesia (n = 9) had significantly shortened left caudate T2 relaxation times when compared to patients without tardive dyskinesia (n = 5). The group of four patients with fewer than 3 months' exposure to neuroleptics demonstrated a significantly greater variability of their left caudate T2 values. T2 relaxation time shortening may be related to iron levels in the basal ganglia and may be of predictive value in evaluating risk of tardive dyskinesia.

    Title Effects of Anticholinergic Agents on Patients with Tardive Dyskinesia and Concomitant Drug-induced Parkinsonism.
    Date January 1990
    Journal Journal of Clinical Psychopharmacology
    Excerpt

    Twenty-five percent of 80 consecutive patients who met research criteria for persistent tardive dyskinesia (TD) were found to have an energy peak in the parkinsonian tremor band (3-6 Hz) of the frequency spectrum of their machine-measured resting hand movements in addition to the abnormalities consistent with TD (increased energy in the 0.5-3 Hz frequency spectrum). Twelve of these patients were studied again in double-blind fashion 2 hours after receiving a placebo and again 2 hours after a single 4 mg dose of trihexyphenidyl hydrochloride (HCl). Compared with the placebo condition, the trihexyphenidyl HCl markedly diminished the measured energy in the 4 Hz band and had no effect or slightly decreased the energy at all other points on the frequency spectrum. Simultaneous Abnormal Involuntary Movement Scale ratings revealed no change in the dyskinetic movements between the conditions; there was a significant subjective improvement reported by the patients following the trihexyphenidyl HCl administration. These observations indicate that electromechanical devices identify a subpopulation of TD patients who may acutely benefit from anticholinergic treatment.

    Title Tardive Dyskinesia in Schizophrenic Patients: Correlation with Negative Symptoms.
    Date August 1989
    Journal Psychiatry Research
    Excerpt

    The relationship between severity of tardive dyskinesia (TD) and the prominence of negative symptoms was assessed in 25 right-handed, medicated schizophrenic patients. TD was quantified using ultrasound detectors and frequency measurement techniques as well as with observer rating scales. Electromechanical studies revealed a systematic relationship between TD severity and negative symptoms; TD was more severe in patients with fewer negative symptoms. The correlation was small in magnitude.

    Title Baep Screening for the Prediction of Tardive Dyskinesia in Schizophrenia.
    Date July 1989
    Journal Psychiatry Research
    Title Comparison of Electromechanical Measures and Observer Ratings of Tardive Dyskinesia.
    Date May 1989
    Journal Psychiatry Research
    Excerpt

    Thirty-three patients with tardive dyskinesia (TD) were studied with multiple-observer consensus ratings of videotaped examinations, ultrasound counts of movement, and electromechanical frequency measures of the movements. There were statistically significant correlations between orofacial ultrasound measures and TD severity determinations made by observers. Clinical ratings did not correlate with frequency measures. Ultrasound measures substantiate observer rating scales, whereas frequency measures appear to provide information not available from clinical rating scale scores.

    Title Lateral Asymmetries of Tardive Dyskinesia in Schizophrenia.
    Date June 1988
    Journal Biological Psychiatry
    Title Effect of 16-16-dimethyl-prostaglandin E2 on Ulceration of Isolated Amphibian Gastric Mucosa.
    Date July 1980
    Journal Gastroenterology
    Excerpt

    In order to investigate the cytoprotective action of 16-16-dimethyl-prostaglandin E2 (16-16D), we studied its effect on sacs of isolated amphibian gastric mucosa known to ulcerate with high frequency in the absence of nutrient HCO3-. The actions of 16-16D, 2.85 X 10(-6) M, were also studied in an in vitro chamber. The incidence of ulceration in HCO3- -free nutrient media containing 10(-4) M histamine was significantly reduced by 16-16D. When artificial gastric juice (AGJ) was instilled into the lumen of the sac, protection occurred only after a pretreatment period of 60 min. Cytoprotection was not observed when active secretion of H+ was inhibited with 10(-3) M metiamide, and AGJ was placed in the lumen of the sac. In open sheets of fundus stimulated with 10(-4) M histamine, 16-16D did not influence H+ secretion. Isc was significantly higher than in control tissues. We conclude that 16-16D is cytoprotective in amphibian gastric mucosa by an action independent of changes in acid secretion or in blood flow. In addition, our studies suggest that 16-16D may increase the availability to the surface cells of nutrient HCO3- produced by actively secreting oxyntic cells.

    Title Effects of Selegiline Pretreatment on Response to Experimental Cocaine Administration
    Date
    Journal Psychiatry Research
    Excerpt

    Several medications have been reported to alter the subjective effects of experimentally administered cocaine. We studied the effects of selegiline, a monoamine oxidase B inhibitor, on the subjective effects of experimentally administered cocaine in chronically cocaine-dependent subjects. Eight subjects completed a protocol that involved repeated administrations of cocaine before and after treatment with selegiline, given in extended release form, 10 mg per day. Four days of treatment with selegiline was associated with decreased self-reported 'high' and 'stimulated' feelings after cocaine administration, measured as the area under the curve. Changes in other subjective effects were less pronounced. Selegiline pretreatment had minimal effects on the cardiovascular responses to cocaine administration.

    Title Human Brain Myelination and Amyloid Beta Deposition in Alzheimer's Disease.
    Date
    Journal Alzheimer's & Dementia : the Journal of the Alzheimer's Association
    Excerpt

    We hypothesized that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte- and myelin-associated iron that promotes amyloid beta (Abeta) oligomerization, its associated toxicity, and the deposition of oligomerized Abeta and iron in neuritic plaques observed in Alzheimer's disease (AD). The model was tested by using published maps of cortical myelination from 1901 and recent in vivo imaging maps of Abeta deposits in humans. The data show that in AD, radiolabeled ligands detect Abeta deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the strikingly lower ability of this imaging ligand to bind Abeta in animal models is consistent with the much lower levels of myelin and associated iron levels in rodents when compared with humans. The hypotheses derived from the "myelin model" are testable with current imaging methods and have important implications for therapeutic interventions that should be expanded to include novel targets such as oligodendrocytes, myelin, and brain iron.

    Title Brain Myelination In Prevalent Neuropsychiatric Developmental Disorders: Primary And Comorbid Addiction.
    Date
    Journal Adolescent Psychiatry
    Excerpt

    Current concepts of addiction focus on neuronal neurocircuitry and neurotransmitters and are largely based on animal model data, but the human brain is unique in its high myelin content and extended developmental (myelination) phase that continues until middle age. The biology of our exceptional myelination process and factors that influence it have been synthesized into a recently published myelin model of human brain evolution and normal development that cuts across the current symptom-based classification of neuropsychiatric disorders.The developmental perspective of the model suggests that dysregulations in the myelination process contribute to prevalent early-life neuropsychiatric disorders, as well as to addictions. These disorders share deficits in inhibitory control functions that likely contribute to their high rates of comorbidity with addiction and other impulsive behaviors. The model posits that substances such as alcohol and psychostimulants are toxic to the extremely vulnerable myelination process and contribute to the poor outcomes of primary and comorbid addictive disorders in susceptible individuals.By increasing the scientific focus on myelination, the model provides a rational biological framework for the development of novel, myelin-centered treatments that may have widespread efficacy across multiple disease states and could potentially be used in treating, delaying, or even preventing some of the most prevalent and devastating neuropsychiatric disorders.

    Title Time-lapse Mapping of Cortical Changes in Schizophrenia with Different Treatments.
    Date
    Journal Cerebral Cortex (new York, N.y. : 1991)
    Excerpt

    Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 +/- 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group x time interactions.

    Title Lifespan Trajectory of Myelin Integrity and Maximum Motor Speed.
    Date
    Journal Neurobiology of Aging
    Excerpt

    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.

    Title Alzheimer's Disease As Homeostatic Responses to Age-related Myelin Breakdown.
    Date
    Journal Neurobiology of Aging
    Excerpt

    The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Abeta) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Abeta production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Abeta deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Abeta and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides "upstream" treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin.

    Title Apolipoprotein E Genotype is Associated with Temporal and Hippocampal Atrophy Rates in Healthy Elderly Adults: A Tensor-based Morphometry Study.
    Date
    Journal Journal of Alzheimer's Disease : Jad
    Excerpt

    Apolipoprotein E (ApoE) ε4 genotype is a strong risk factor for developing Alzheimer's disease (AD). Conversely, the presence of the ε2 allele has been shown to mitigate cognitive decline. Tensor-based morphometry (TBM), a novel computational approach for visualizing longitudinal progression of brain atrophy, was used to determine whether cognitively intact elderly participants with the ε4 allele demonstrate greater volume reduction than those with the ε2 allele. Healthy "younger elderly" volunteers, aged 55-75, were recruited from the community and hospital staff. They were evaluated with a baseline and follow-up MRI scan (mean scan interval = 4.72 years, s.d. = 0.55) and completed ApoE genotyping. Twenty-seven participants were included in the study of which 16 had the ε4 allele (all heterozygous ε3ε4 genotype) and 11 had the ε2ε3 genotype. The two groups did not differ significantly on any demographic characteristics and all subjects were cognitively "normal" at both baseline and follow-up time points. TBM was used to create 3D maps of local brain tissue atrophy rates for individual participants; these spatially detailed 3D maps were compared between the two ApoE groups. Regional analyses were performed and the ε4 group demonstrated significantly greater annual atrophy rates in the temporal lobes (p = 0.048) and hippocampus (p = 0.016); greater volume loss was observed in the right hippocampus than the left. TBM appears to be useful in tracking longitudinal progression of brain atrophy in cognitively asymptomatic adults. Possession of the ε4 allele is associated with greater temporal and hippocampal volume reduction well before the onset of cognitive deficits.


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