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1.  The Early Longitudinal Course of Cognitive Deficits in Schizophrenia 
Cognitive impairment is a core feature of schizophrenia. However, the longitudinal course and pattern of this impairment, and its relationship to functional outcome is not fully understood. Among the likely factors in the persistence of cognitive deficits in schizophrenia are brain tissue changes over time, which in turn appear to be related to antipsychotic medication adherence.
Cognitive deficits are viewed as a core feature of schizophrenia primarily because cognitive deficits clearly exist before the onset of psychosis and can predict illness onset among those at high risk of developing the illness. Additionally, these deficits often persist during symptomatic remissions in patients, and are relatively stable across time both in patients and in individuals at risk for schizophrenia.
Despite clear evidence that cognitive impairment can predict functional outcome in chronic schizophrenia, results of studies examining this relationship in the early phase of psychosis have been mixed. Recent data, however, strongly suggest that interventions targeting early cognitive deficits may be crucial to the prevention of chronic disability, and thus should be a prominent target for therapy.
Finally, it is vital to keep schizophrenia patients consistently on their antipsychotic medications. A novel method of examining intracortical myelin volume indicated that the choice of antipsychotic treatment had a differential impact on frontal myelination. These data suggest that long acting injectable antipsychotic medication may prevent patients from declining further through a combination of better adherence and pharmacokinetics.
PMCID: PMC4081490  PMID: 24919168
2.  Cigarette Smoking and White Matter Microstructure 
Psychopharmacology  2012;221(2):285-295.
Diffusion tensor imaging has been used before in testing associations between cigarette smoking and white matter integrity, with inconsistent results. Published reports indicate higher fractional anisotropy (FA) in some brain regions and lower FA in others in adult smokers compared to nonsmokers. Adolescent smokers exhibited elevated FA at several sites and a positive correlation of FA in the genu corpus callosum with exposure to smoking (pack-years).
To help resolve prior discrepancies, we studied adults, sampling multiple brain regions, and testing for relationships to clinical features of nicotine dependence and exposure to smoking.
Brain MRI scans (1.5T) were acquired, and FA and apparent diffusion coefficient (ADC) were assayed in corpus callosum and prefrontal white matter, corona radiata, internal capsule, cingulum bundle, and hippocampal perforant fibers in 18 smokers (33.7±7.9 years of age) and 18 age- and gender-matched nonsmokers.
ADC showed no group difference, but smokers had higher (4.3-21.1%) FA than nonsmokers. The differences were significant in right prefrontal white matter, cingulum, and genu corpus callosum. FA in several regions was negatively correlated with nicotine dependence or cigarettes/day.
Combined with earlier findings, these results suggest a model of changing trajectories whereby FA is higher with tobacco exposure during adolescence, and declines with continued smoking in adulthood. This notion is supported by the observation that, at multiple sampling sites, participants who had started smoking earlier in life had higher FA than those who had started later.
PMCID: PMC4111107  PMID: 22215225
white matter; diffusion tensor imaging; nicotine dependence; magnetic resonance imaging; fractional anisotropy; tobacco
3.  DTI Tractography and White Matter Fiber Tract Characteristics in Euthymic Bipolar I Patients and Healthy Control Subjects 
Brain imaging and behavior  2013;7(2):129-139.
With the introduction of diffusion tensor imaging (DTI), structural differences in white matter (WM) architecture between psychiatric populations and healthy controls can be systematically observed and measured. In particular, DTI-tractography can be used to assess WM characteristics over the entire extent of WM tracts and aggregated fiber bundles. Using 64-direction DTI scanning in 27 participants with bipolar disorder (BD) and 26 age-and-gender-matched healthy control subjects, we compared relative length, density, and fractional anisotrophy (FA) of WM tracts involved in emotion regulation or theorized to be important neural components in BD neuropathology. We interactively isolated 22 known white matter tracts using region-of-interest placement (TrackVis software program) and then computed relative tract length, density, and integrity. BD subjects demonstrated significantly shorter WM tracts in the genu, body and splenium of the corpus callosum compared to healthy controls. Additionally, bipolar subjects exhibited reduced fiber density in the genu and body of the corpus callosum, and in the inferior longitudinal fasciculus bilaterally. In the left uncinate fasciculus, however, BD subjects exhibited significantly greater fiber density than healthy controls. There were no significant differences between groups in WM tract FA for those tracts that began and ended in the brain. The significance of differences in tract length and fiber density in BD is discussed.
PMCID: PMC3572298  PMID: 23070746
4.  Regional Differences in White Matter Breakdown Between Frontotemporal Dementia and Early-Onset Alzheimer's Disease1 
White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).
Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting.
We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale of Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants.
Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group.
The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.
PMCID: PMC3947877  PMID: 24150110
Alzheimer's disease; behavioral variant; diffusion tensor imaging; early onset; frontotemporal dementia; magnetic resonance imaging; myelin; white matter
5.  Survey of Protocols for the Manual Segmentation of the Hippocampus: Preparatory Steps Towards a Joint EADC-ADNI Harmonized Protocol 
Journal of Alzheimer's disease : JAD  2011;26(0 3):10.3233/JAD-2011-0004.
Manual segmentation from magnetic resonance imaging (MR) is the gold standard for evaluating hippocampal atrophy in Alzheimer’s disease (AD). Nonetheless, different segmentation protocols provide up to 2.5-fold volume differences. Here we surveyed the most frequently used segmentation protocols in the AD literature as a preliminary step for international harmonization. The anatomical landmarks (anteriormost and posteriormost slices, superior, inferior, medial, and lateral borders) were identified from 12 published protocols for hippocampal manual segmentation ([Abbreviation] first author, publication year: [B] Bartzokis, 1998; [C] Convit, 1997; [dTM] deToledo-Morrell, 2004; [H] Haller, 1997; [J] Jack, 1994; [K] Killiany, 1993; [L] Lehericy, 1994; [M] Malykhin, 2007; [Pa] Pantel, 2000; [Pr] Pruessner, 2000; [S] Soininen, 1994; [W] Watson, 1992). The hippocampi of one healthy control and one AD patient taken from the 1.5T MR ADNI database were segmented by a single rater according to each protocol. The accuracy of the protocols’ interpretation and translation into practice was checked with lead authors of protocols through individual interactive web conferences. Semantically harmonized landmarks and differences were then extracted, regarding: (a) the posteriormost slice, protocol [B] being the most restrictive, and [H, M, Pa, Pr, S] the most inclusive; (b) inclusion [C, dTM, J, L, M, Pr, W] or exclusion [B, H, K, Pa, S] of alveus/fimbria; (c) separation from the parahippocampal gyrus, [C] being the most restrictive, [B, dTM, H, J, Pa, S] the most inclusive. There were no substantial differences in the definition of the anteriormost slice. This survey will allow us to operationalize differences among protocols into tracing units, measure their impact on the repeatability and diagnostic accuracy of manual hippocampal segmentation, and finally develop a harmonized protocol.
PMCID: PMC3829626  PMID: 21971451
Hippocampus; manual segmentation protocol; harmonization; anatomical landmark; Alzheimer’s disease; manual tracing; medial temporal lobes; atrophy; degeneration; MRI
6.  Pre-menopausal Hysterectomy Is Associated With Increased Brain Ferritin Iron 
Neurobiology of Aging  2011;33(9):1950-1958.
Iron is essential for triggering oligodendrocytes to myelinate, however, in gray matter (GM) iron increases with age and is associated with age-related degenerative brain diseases. Women have lower iron levels than men, both in the periphery and in the brain, particularly in white matter (WM), possibly due to iron loss through menstruation. We tested the hypothesis that hysterectomy could increase WM iron levels.
We assessed three WM and five GM regions in 39 post-menopausal women, of whom 15 had premenopausal hysterectomy, utilizing a validated magnetic resonance imaging technique called FDRI that quantifies ferritin iron. A group of 54 matched male subjects was included for comparison.
Amongst women, hysterectomy was associated with significantly higher frontal lobe WM iron. Men had higher iron levels than women without hysterectomy in three brain regions but did not differ from women with hysterectomy in any region.
The results suggest that menstruation-associated blood loss is a source of gender differences in brain iron. It is possible that brain iron can be influenced by peripheral iron levels and may thus be a modifiable risk factor for age-related degenerative diseases.
PMCID: PMC3245348  PMID: 21925770
hysterectomy; iron; metal; dementia; risk; gender; myelin; oligodendrocytes; white matter; gray matter; treatment; prevention
7.  Impact on Intracortical Myelination Trajectory of Long Acting Injection Versus Oral Risperidone in First-Episode Schizophrenia 
Schizophrenia research  2012;140(1-3):122-128.
Imaging and post-mortem studies suggest that frontal lobe intracortical myelination is dysregulated in schizophrenia (SZ). Prior MRI studies suggested that early in treatment of SZ, antipsychotic medications initially increase frontal lobe intracortical myelin (ICM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of ICM decline in chronic SZ is due to medication non-adherence or pharmacokinetics, it may be modifiable by long acting injection (LAI) formulations.
Assess the effect of risperidone formulation on the ICM trajectory during a six-month randomized trial of LAI (RLAI) versus oral (RisO) in first-episode SZ subjects.
Two groups of SZ subjects (RLAI, N=9; and RisO, N=13) matched on pre-randomization oral medication exposure were prospectively examined at baseline and six months later, along with 12 healthy controls (HCs). Frontal lobe ICM volume was assessed using inversion recovery (IR) and proton density (PD) MRI images. Medication adherence was tracked.
Main outcome measure
ICM volume change scores adjusted for the change in the HCs.
ICM volume increased significantly (p=.005) in the RLAI and non-significantly (p=.39) in the RisO groups compared to the healthy controls. A differential between-group treatment effect was at a trend level (p=.093). SZ subjects receiving RLAI had better medication adherence and more ICM increases (chi-square p<.05).
The results suggest that RLAI may promote ICM development in first-episode SZ patients. Better adherence and/or pharmacokinetics provided by LAI may modify the ICM trajectory. In vivo MRI myelination measures can help clarify pharmacotherapeutic mechanisms of action.
PMCID: PMC3567927  PMID: 22809684
antipsychotic; medication; dopamine; second generation; atypical; myelin; white matter; gray matter; oligodendrocyte; development; aging
8.  Mood-state effects on amygdala volume in bipolar disorder 
Journal of Affective Disorders  2012;139(3):298-301.
Prior structural neuroimaging studies of the amygdala in patients with bipolar disorder have reported higher or lower volumes, or no difference relative to healthy controls. These inconsistent findings may have resulted from combining subjects in different mood states. The prefrontal cortex has recently been reported to have a lower volume in depressed versus euthymic bipolar patients. Here we examined whether similar mood state-dependent volumetric differences are detectable in the amygdala.
Forty subjects, including 28 with bipolar disorder type I (12 depressed and 16 euthymic), and 12 healthy comparison subjects were scanned on a 3T magnetic resonance image (MRI) scanner. Amygdala volumes were manually traced and compared across subject groups, adjusting for sex and total brain volume.
Statistical analyses found a significant effect of mood state and hemisphere on amygdala volume. Subsequent comparisons revealed that amygdala volumes were significantly lower in the depressed bipolar group compared to both the euthymic bipolar (p=0.005) and healthy control (p=0.043) groups.
Our study was cross-sectional and some patients were medicated.
Our results suggest that mood state influences amygdala volume in subjects with bipolar disorder. Future studies that replicate these findings in unmedicated patient samples scanned longitudinally are needed.
PMCID: PMC3372678  PMID: 22521854
Bipolar Disorder; Depression; Magnetic resonance imaging; MRI; Amygdala
9.  Neuroglialpharmacology: Myelination As A Shared Mechanism of Action of Psychotropic Treatments 
Neuropharmacology  2012;62(7):2137-2153.
Current psychiatric diagnostic schema segregate symptom clusters into discrete entities, however, large proportions of patients suffer from comorbid conditions that fit neither diagnostic nor therapeutic schema. Similarly, psychotropic treatments ranging from lithium and antipsychotics to serotonin reuptake inhibitors (SSRIs) and acetylcholinesterase inhibitors have been shown to be efficacious in a wide spectrum of psychiatric disorders ranging from autism, schizophrenia (SZ), depression, and bipolar disorder (BD) to Alzheimer’s disease (AD). This apparent lack of specificity suggests that psychiatric symptoms as well as treatments may share aspects of pathophysiology and mechanisms of action that defy current symptom-based diagnostic and neuron-based therapeutic schema.
A myelin-centered model of human brain function can help integrate these incongruities and provide novel insights into disease etiologies and treatment mechanisms. Available data are integrated herein to suggest that widely used psychotropic treatments ranging from antipsychotics and antidepressants to lithium and electroconvulsive therapy share complex signaling pathways such as Akt and glycogen synthase kinase-3 (GSK3) that affect myelination, its plasticity, and repair. These signaling pathways respond to neurotransmitters, neurotrophins, hormones, and nutrition, underlie intricate neuroglial communications, and may substantially contribute to the mechanisms of action and wide spectra of efficacy of current therapeutics by promoting myelination. Imaging and genetic technologies make it possible to safely and noninvasively test these hypotheses directly in humans and can help guide clinical trial efforts designed to correct myelination abnormalities. Such efforts may provide insights into novel avenues for treatment and prevention of some of the most prevalent and devastating human diseases.
Pervasive brain myelination underlies neural network synchrony and our distinctiveness as a species. Psychiatric diagnoses may share deficits in myelin development, plasticity, or repair. Treatments act on neuroglial signaling pathways such as Akt and GSK3 that improve myelination. Treatment efficacy may derive from myelination-driven improved neural network synchronization. “Neuroglialpharmacology” encapsulates a paradigm shift in medication development strategy.
PMCID: PMC3586811  PMID: 22306524
White matter; oligodendrocyte; intracortical myelin; medication; MRI; NG2 cells; neuregulin; ErbB; DISC1; IGF1; Reelin; Cdk; MAPK; mTOR; Leptin
10.  Depressive Symptoms in Mild Cognitive Impairment Predict Greater Atrophy in Alzheimer’s Disease-Related Regions 
Biological Psychiatry  2012;71(9):814-821.
Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and may be a potential clinical marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Using tensor-based morphometry (TBM), we examined the longitudinal neuroanatomical changes associated with depressive symptoms in MCI.
243 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had brain MRI scans at baseline and 2-year follow-up were classified into depressed (DEP, n=44), non-depressed with other neuropsychiatric symptoms (OTHER, n=93), and no-symptom (NOSYMP, n=106) groups based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). TBM was used to create individual 3D-maps of 2-year brain changes that were compared between groups.
DEP subjects had more frontal (p=0.024), parietal (p=0.030), and temporal (p=0.038) white matter atrophy than NOSYMP subjects. A subset of DEP subjects whose depressive symptoms persisted over 2-years also had higher conversion to AD and more decline on measures of global cognition, language abilities, and executive functioning compared to stable NOSYMP subjects. OTHER and NOSYMP groups exhibited no differences in rates of atrophy.
Depressive symptoms in MCI subjects were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes including prodromal AD. Thus, assessment of depressive symptoms may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD.
PMCID: PMC3322258  PMID: 22322105
Depression; Mild Cognitive Impairment; Alzheimer’s Disease; Neuropsychiatric Symptoms; Tensor-Based Morphometry; White Matter
11.  Predicting missing biomarker data in a longitudinal study of Alzheimer disease 
Lo, Raymond Y. | Jagust, William J. | Aisen, Paul | Jack, Clifford R. | Toga, Arthur W. | Beckett, Laurel | Gamst, Anthony | Soares, Holly | C. Green, Robert | Montine, Tom | Thomas, Ronald G. | Donohue, Michael | Walter, Sarah | Dale, Anders | Bernstein, Matthew | Felmlee, Joel | Fox, Nick | Thompson, Paul | Schuff, Norbert | Alexander, Gene | DeCarli, Charles | Bandy, Dan | Chen, Kewei | Morris, John | Lee, Virginia M.-Y. | Korecka, Magdalena | Crawford, Karen | Neu, Scott | Harvey, Danielle | Kornak, John | Saykin, Andrew J. | Foroud, Tatiana M. | Potkin, Steven | Shen, Li | Buckholtz, Neil | Kaye, Jeffrey | Dolen, Sara | Quinn, Joseph | Schneider, Lon | Pawluczyk, Sonia | Spann, Bryan M. | Brewer, James | Vanderswag, Helen | Heidebrink, Judith L. | Lord, Joanne L. | Petersen, Ronald | Johnson, Kris | Doody, Rachelle S. | Villanueva-Meyer, Javier | Chowdhury, Munir | Stern, Yaakov | Honig, Lawrence S. | Bell, Karen L. | Morris, John C. | Mintun, Mark A. | Schneider, Stacy | Marson, Daniel | Griffith, Randall | Clark, David | Grossman, Hillel | Tang, Cheuk | Marzloff, George | Toledo-Morrell, Leylade | Shah, Raj C. | Duara, Ranjan | Varon, Daniel | Roberts, Peggy | Albert, Marilyn S. | Pedroso, Julia | Toroney, Jaimie | Rusinek, Henry | de Leon, Mony J | De Santi, Susan M | Doraiswamy, P. Murali | Petrella, Jeffrey R. | Aiello, Marilyn | Clark, Christopher M. | Pham, Cassie | Nunez, Jessica | Smith, Charles D. | Given, Curtis A. | Hardy, Peter | Lopez, Oscar L. | Oakley, MaryAnn | Simpson, Donna M. | Ismail, M. Saleem | Brand, Connie | Richard, Jennifer | Mulnard, Ruth A. | Thai, Gaby | Mc-Adams-Ortiz, Catherine | Diaz-Arrastia, Ramon | Martin-Cook, Kristen | DeVous, Michael | Levey, Allan I. | Lah, James J. | Cellar, Janet S. | Burns, Jeffrey M. | Anderson, Heather S. | Laubinger, Mary M. | Bartzokis, George | Silverman, Daniel H.S. | Lu, Po H. | Graff-Radford MBBCH, Neill R | Parfitt, Francine | Johnson, Heather | Farlow, Martin | Herring, Scott | Hake, Ann M. | van Dyck, Christopher H. | MacAvoy, Martha G. | Benincasa, Amanda L. | Chertkow, Howard | Bergman, Howard | Hosein, Chris | Black, Sandra | Graham, Simon | Caldwell, Curtis | Hsiung, Ging-Yuek Robin | Feldman, Howard | Assaly, Michele | Kertesz, Andrew | Rogers, John | Trost, Dick | Bernick, Charles | Munic, Donna | Wu, Chuang-Kuo | Johnson, Nancy | Mesulam, Marsel | Sadowsky, Carl | Martinez, Walter | Villena, Teresa | Turner, Scott | Johnson, Kathleen B. | Behan, Kelly E. | Sperling, Reisa A. | Rentz, Dorene M. | Johnson, Keith A. | Rosen, Allyson | Tinklenberg, Jared | Ashford, Wes | Sabbagh, Marwan | Connor, Donald | Jacobson, Sandra | Killiany, Ronald | Norbash, Alexander | Nair, Anil | Obisesan, Thomas O. | Jayam-Trouth, Annapurni | Wang, Paul | Lerner, Alan | Hudson, Leon | Ogrocki, Paula | DeCarli, Charles | Fletcher, Evan | Carmichael, Owen | Kittur, Smita | Mirje, Seema | Borrie, Michael | Lee, T-Y | Bartha, Dr Rob | Johnson, Sterling | Asthana, Sanjay | Carlsson, Cynthia M. | Potkin, Steven G. | Preda, Adrian | Nguyen, Dana | Tariot, Pierre | Fleisher, Adam | Reeder, Stephanie | Bates, Vernice | Capote, Horacio | Rainka, Michelle | Hendin, Barry A. | Scharre, Douglas W. | Kataki, Maria | Zimmerman, Earl A. | Celmins, Dzintra | Brown, Alice D. | Gandy, Sam | Marenberg, Marjorie E. | Rovner, Barry W. | Pearlson, Godfrey | Anderson, Karen | Saykin, Andrew J. | Santulli, Robert B. | Englert, Jessica | Williamson, Jeff D. | Sink, Kaycee M. | Watkins, Franklin | Ott, Brian R. | Wu, Chuang-Kuo | Cohen, Ronald | Salloway, Stephen | Malloy, Paul | Correia, Stephen | Rosen, Howard J. | Miller, Bruce L. | Mintzer, Jacobo
Neurology  2012;78(18):1376-1382.
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.
CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.
The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
PMCID: PMC3345787  PMID: 22491869
12.  Patterns of Brain Atrophy in Clinical Variants of Frontotemporal Lobar Degeneration 
The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups.
Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects.
Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology.
The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.
PMCID: PMC3609420  PMID: 23306166
Frontotemporal dementia; Primary progressive aphasia; Longitudinal study; Magnetic resonance imaging; Tensor-based morphometry; White matter
13.  Age-Related Slowing in Cognitive Processing Speed is Associated with Myelin Integrity in a Very Healthy Elderly Sample 
Performance on measures of cognitive processing speed (CPS) slows with age, but the biological basis associated with this cognitive phenomenon remains incompletely understood. We assessed the hypothesis that the age-related slowing in CPS is associated with myelin breakdown in late-myelinating regions in a very healthy elderly population. An in vivo MRI biomarker of myelin integrity was obtained from the prefrontal lobe white matter and the genu of the corpus callosum for 152 healthy elderly adults. These regions myelinate later in brain development and are more vulnerable to breakdown due to the effects of normal aging. To evaluate regional specificity, we also assessed the splenium of the corpus callosum as a comparison region, which myelinates early in development and primarily contains axons involved in visual processing. The measure of myelin integrity was significantly correlated with CPS in highly vulnerable late-myelinating regions but not in the splenium. These results have implications for the neurobiology of the cognitive changes associated with brain aging.
PMCID: PMC3269444  PMID: 22133139
Healthy Aging; Cognition; Information Processing Speed; Myelin; White Matter; Magnetic Resonance Imaging; Alzheimer’s Disease; Dementia
14.  Long Acting Injection Versus Oral Risperidone in First-Episode Schizophrenia: Differential Impact on White Matter Myelination Trajectory 
Schizophrenia research  2011;132(1):35-41.
Imaging and post-mortem studies provide converging evidence that subjects with schizophrenia (SZ) have a dysregulated trajectory of frontal lobe myelination. Prior MRI studies suggested that early in treatment of SZ, antipsychotic medications initially increase frontal lobe white matter (WM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of WM decline associated with chronic disease may be due to medication non-adherence, it may be modifiable by long acting injection (LAI) formulations.
Examine the impact of antipsychotic formulation on the myelination trajectory during a randomized six-month trial of LAI risperidone (RLAI) versus oral risperidone (RisO) in first-episode SZ subjects.
Two groups of SZ subjects (RLAI, N=11; and RisO, N=13) that were matched in pre-randomization oral medication exposure and 14 healthy controls (HCs) were prospectively examined. Frontal lobe WM volume was estimated using inversion recovery (IR) MRI images. A brief neuropsychological battery that focused on reaction times was performed at the end of the study.
Main outcome measure
WM volume change scores.
WM volume remained stable in the RLAI and decreased significantly in the RisO groups resulting in a significant differential treatment effect, while the HC had a WM change intermediate and not significantly different from the two SZ groups. WM increase was associated with faster reaction times in tests involving frontal lobe function.
The results suggest that RLAI may improve the trajectory of myelination in first-episode patients and have a beneficial impact on cognitive performance. Better adherence provided by LAI may underlie the modified trajectory of myelin development. In vivo MRI biomarkers of myelination can help clarify mechanisms of action of treatment interventions.
PMCID: PMC3172389  PMID: 21767934
antipsychotic; medication; dopamine; second generation; atypical; myelin; white matter; gray matter; oligodendrocyte; development; aging
15.  Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging 
Neuropsychopharmacology  2011;36(7):1375-1384.
Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON−) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON− status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=−0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON− group (r=−0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.
PMCID: PMC3096807  PMID: 21389980
memory; iron; gene; sex; dementia; treatment; aging/geriatrics; imaging; clinical or preclinical; learning & memory; neurogenetics; metal; myelin; oligodendrocytes; prevention; risk
16.  Oligodendrocytes in Schizophrenia 
PMCID: PMC3420671  PMID: 22937262
17.  Lifespan trajectory of myelin integrity and maximum motor speed 
Neurobiology of aging  2008;31(9):1554-1562.
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.
A sensitive in vivo MRI biomarker of myelin integrity (calculated transverse relaxation rates (R2)) 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, R2 of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured.
FLwm R2 and FTS measures were significantly correlated (r = .45, p < .0001) with no association noted in the early-myelinating region (splenium). Both FLwm R2 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.
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 R2 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.
PMCID: PMC2888859  PMID: 18926601
Age; Processing speed; Motor; White matter; Oligodendrocyte; Breakdown; Cognition; Dementia; Risk; Neurodegeneration; Alzheimer; Onset; Frontal lobe; Treatment; Prevention
18.  Alzheimer’s disease as homeostatic responses to age-related myelin breakdown 
Neurobiology of aging  2009;32(8):1341-1371.
The amyloid hypothesis (AH) of Alzheimer’s disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ 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 Aβ 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 Aβ 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.
PMCID: PMC3128664  PMID: 19775776
Aging; Oligodendrocyte; Peroxisome; BACE; Neuregulin; Apolipoprotein; Prevention; Ubiquitin; α-Synuclein; TDP-43; FTLD
19.  Prevalent Iron Metabolism Gene Variants Associated with Increased Brain Ferritin Iron in Healthy Older Men 
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.
PMCID: PMC3119253  PMID: 20164577
Alpha synuclein; amyloid; basal ganglia; chelation; dementia; diet; free radicals; gene; gray matter; iron; Lewy body; metal; myelin; oligodendrocytes; prevention; risk; tau; treatment
20.  Therapeutics for cognitive aging 
Annals of the New York Academy of Sciences  2010;1191(Suppl 1):E1-15.
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.
PMCID: PMC3107251  PMID: 20392284
21.  Apolipoprotein E Genotype is Associated with Temporal and Hippocampal Atrophy Rates in Healthy Elderly Adults: A Tensor-Based Morphometry Study1 
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.
PMCID: PMC3107252  PMID: 21098974
Aging; Alzheimer’s disease; Apolipoprotein E; asymmetry; healthy elderly; hippocampus; magnetic resonance imaging; tensor-based morphometry; temporal lobe; white matter
22.  Diagnosing Depression in Alzheimer Disease With the National Institute of Mental Health Provisional Criteria 
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.
Descriptive longitudinal cohort study.
The Alzheimer’s Disease Research Centers of California.
A cohort of 101 patients meeting NINDS-ADRDA criteria for possible/probable AD, intentionally selected to increase the frequency of depression at baseline.
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.
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 (κ = 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.
The NIMH-dAD criteria identify a greater proportion of AD patients as depressed than several other established tools.
PMCID: PMC2989660  PMID: 18515691
23.  In-Vivo evidence of differential impact of typical and atypical antipsychotics on intracortical myelin in adults with schizophrenia 
Schizophrenia research  2009;113(2-3):322-331.
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.
In a follow-up reanalysis of MRI images from the original study, we used a novel method to assess whether the difference in WM volumes could be caused by a differential effect of medications on the intracortical myelination process.
Design, setting, and participants
Two different male cohorts of healthy controls ranging in age from 18–35 years were compared to cohorts of subjects with schizophrenia who were treated with either oral risperidone (Ris) or fluphenazine decanoate (Fd).
Main outcome measure
A novel MRI method that combines the distinct tissue contrasts provided by IR and proton density (PD) images was used to estimate intracortical myelin (ICM) volume.
When compared with their pooled healthy control comparison group, the two groups of schizophrenic patients differed in the frontal lobe ICM measure with the Ris group having significantly higher volume.
The data suggest that in adults with schizophrenia antipsychotic treatment choice may be specifically and differentially impacting later-myelinating intracortical circuitry. In vivo MRI can be used to dissect subtle differences in brain tissue characteristics and thus help clarify the effect of pharmacologic treatments on developmental and pathologic processes.
PMCID: PMC2862048  PMID: 19616412
Schizophrenia; second generation antipsychotic medication; atypical; intracortical myelin; white matter; gray matter; oligodendrocyte; trajectory; development; lipid; age; prevention
24.  Time-Lapse Mapping of Cortical Changes in Schizophrenia with Different Treatments 
Cerebral Cortex (New York, NY)  2008;19(5):1107-1123.
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 × time interactions.
PMCID: PMC2665155  PMID: 18842668
cortex; development; imaging; neurotoxicity; schizophrenia
25.  White-matter abnormalities in brain during early abstinence from methamphetamine abuse 
Psychopharmacology  2010;209(1):13-24.
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.
Using diffusion tensor imaging at 1.5 T, fractional anisotropy (FA) was measured in prefrontal white matter at four inferior–superior levels parallel to the anterior commissure–posterior commissure (AC–PC) plane. We also sampled FA in the corpus callosum at the midline and at eight bilateral, fiber-tract sites in other regions implicated in effects of methamphetamine.
The methamphetamine group exhibited lower FA in right prefrontal white matter above the AC–PC plane (11.9% lower; p = 0.007), in midline genu corpus callosum (3.9%; p = 0.019), in left and right midcaudal superior corona radiata (11.0% in both hemispheres, p’s = 0.020 and 0.016, respectively), and in right perforant fibers (7.3%; p = 0.025). FA in left midcaudal superior corona radiata was correlated with depressive and generalized psychiatric symptoms within the methamphetamine group.
The findings support the idea that methamphetamine abuse produces microstructural abnormalities in white matter underlying and interconnecting prefrontal cortices and hippocampal formation. These effects are already present during the first weeks of abstinence from methamphetamine and are linked to psychiatric symptoms assessed during this period.
PMCID: PMC2819660  PMID: 20101394
Diffusion tensor imaging (DTI); Methamphetamine; Frontal white matter; Corpus callosum; Perforant path; Psychiatric symptoms

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