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1.  An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice 
Science translational medicine  2014;6(236):236re4.
Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), decreased Aβ in brain interstitial fluid (ISF) in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of pre-existing plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable-isotope labeling kinetics (SILK), with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.
doi:10.1126/scitranslmed.3008169
PMCID: PMC4269372  PMID: 24828079
2.  Bootstrapping GEE models for fMRI regional connectivity 
NeuroImage  2012;63(4):1890-1900.
An Alzheimer’s fMRI study has motivated us to evaluate inter-regional correlations during rest between groups. We apply generalized estimating equation (GEE) models to test for differences in regional correlations across groups. Both the GEE marginal model and GEE transition model are evaluated and compared to the standard pooling Fisher-z approach using simulation studies. Standard errors of all methods are estimated both theoretically (model-based) and empirically (bootstrap). Of all the methods, we find that the transition models have the best statistical properties. Overall, the model-based standard errors and bootstrap standard errors perform about the same. We also demonstrate the methods with a functional connectivity study in a healthy cognitively normal population of ApoE4+ participants and ApoE4− participants who are recruited from the Adult Children’s Study conducted at the Washington University Knight Alzheimer’s Disease Research Center.
doi:10.1016/j.neuroimage.2012.08.036
PMCID: PMC3491908  PMID: 22906513
resting-state fMRI; time-series; temporal dependence; brain regional correlations; functional connectivity
3.  Depression and the Hippocampus: Cause or Effect? 
Biological psychiatry  2011;70(4):308-309.
doi:10.1016/j.biopsych.2011.06.006
PMCID: PMC3733566  PMID: 21791257
Depression; Hippocampus
4.  Diminished performance on neuropsychological testing in late life depression is correlated with microstructural white matter abnormalities 
Neuroimage  2012;60(4):2182-2190.
Background
Traditional T2 weighted MR imaging results are non-specific for the extent of underlying white matter structural abnormalities present in late life depression (LLD). Diffusion tensor imaging provides a unique opportunity to investigate the extent and nature of structural injury, but has been limited by examining only a subset of regions of interest (ROI) and by confounds common to the study of an elderly population, including comorbid vascular pathology. Furthermore, comprehensive correlation of diffusion tensor imaging (DTI) measurements, including axial and radial diffusivity measurements, has not been demonstrated in the late life depression population.
Methods
51 depressed and 16 non-depressed, age- and cerebrovascular risk factor- matched elderly subjects underwent traditional anatomic T1 and T2 weight imaging, as well as DTI. The DTI data were skeletonized using tract based spatial statistics (TBSS), and both regional and global analyses were performed.
Results
Widespread structural abnormalities within white matter were detected in the LLD group, accounting for age, gender and education and matched for cerebrovascular risk factors and global T2 white matter hyperintensities (T2WMH). Regional differences were most prominent in uncinate and cingulate white matter and were generally characterized by an increase in radial diffusivity. Age-related changes particularly in the cingulate bundle were more advanced in individuals with LLD relative to controls. Regression analysis demonstrated significant correlations of regional fractional anisotropy and radial diffusivity with five different neuropsychological factor scores. TBSS analysis demonstrated a greater extent of white matter abnormalities in LLD not responsive to treatment, as compared to controls.
Conclusions
White matter integrity is compromised in late life depression, largely manifested by increased radial diffusivity in specific regions, suggesting underlying myelin injury. A possible mechanism for underlying myelin injury is chronic white matter ischemia related to intrinsic cerebrovascular disease. In some regions such as the cingulate bundle, the white matter injury related to late-life depression appears to be independent of and compounded by age-related changes. The correlations with neuropsychological testing indicate the essential effects of white matter injury on functional status. Lastly, response to treatment may depend on the extent of white matter injury, suggesting a need for intact functional networks.
doi:10.1016/j.neuroimage.2012.02.044
PMCID: PMC3337766  PMID: 22487548
Diffusion tensor imaging; Tract based spatial statistics; Anisotropy; Radial diffusivity
5.  Resting State Functional Connectivity in Preclinical Alzheimer’s Disease: A Review 
Biological psychiatry  2013;74(5):340-347.
There has been a dramatic increase in the number of studies using resting state fMRI, a recent addition to imaging analysis techniques. The technique analyzes ongoing low frequency fluctuations in the blood oxygen level dependent (BOLD) signal. Through patterns of spatial coherence, these fluctuations can be used to identify the networks within the brain. Multiple brain networks are present simultaneously and the relationships within and between networks are in constant dynamic flux. Resting state fMRI functional connectivity (rs-fMRI) analysis is increasingly used to detect subtle brain network differences, and in the case of pathophysiology, subtle abnormalities in illnesses such as Alzheimer’s disease (AD). The sequence of events leading up to dementia has been hypothesized to begin many years or decades before any clinical symptoms occur. Here we review the findings across rs-fMRI studies in the spectrum of preclinical AD to clinical AD. In addition, we discuss evidence for underlying preclinical AD mechanisms, including an important relationship between resting state functional connectivity and brain metabolism, and how this results in a distinctive pattern of amyloid plaque deposition in default mode network regions.
doi:10.1016/j.biopsych.2012.11.028
PMCID: PMC3537262  PMID: 23290495
fMRI; BOLD; amyloid; precuneus; default mode network (DMN); glycolysis
6.  Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression 
Brain stimulation  2013;6(5):788-797.
Background
Vagus nerve stimulation (VNS) has antidepressant effects in treatment resistant major depression (TRMD); these effects are poorly understood. This trial examines associations of subacute (3 months) and chronic (12 months) VNS with cerebral metabolism in TRMD.
Objective
17Fluorodeoxyglucose positron emission tomography was used to examine associations between 12-month antidepressant VNS response and cerebral metabolic rate for glucose (CMRGlu) changes at 3 and 12 months.
Methods
Thirteen TRMD patients received 12 months of VNS. Depression assessments (Hamilton Depression Rating Scale [HDRS]) and PET scans were obtained at baseline (pre-VNS) and 3/12 months. CMRGlu was assessed in eight a priori selected brain regions (bilateral anterior insular [AIC], orbitofrontal [OFC], dorsolateral prefrontal [DLPFC], and anterior cingulate cortices [ACC]). Regional CMRGlu changes over time were studied in VNS responders (decreased 12 month HDRS by ≥50%) and nonresponders.
Results
A significant trend (decreased 3 month CMRGlu) in the right DLPFC was observed over time in VNS responders (n = 9; P = 0.006). An exploratory whole brain analysis (Puncorrected = 0.005) demonstrated decreased 3 month right rostral cingulate and DLPFC CMRGlu, and increased 12 month left ventral tegmental CMRGlu in responders.
Conclusions/Limitations
VNS response may involve gradual (months in duration) brain adaptations. Early on, this process may involve decreased right-sided DLPFC/cingulate cortical activity; longer term effects (12 months) may lead to brainstem dopaminergic activation. Study limitations included: a) a small VNS nonresponders sample (N = 4), which limited conclusions about nonresponder CMRGlu changes; b) no control group; and, c) patients maintained their psychotropic medications.
doi:10.1016/j.brs.2012.11.006
PMCID: PMC3954813  PMID: 23485649
Treatment resistant depression; Vagus nerve stimulation; Positron emission tomography; Depression; Antidepressant
7.  Regional White Matter Hyperintensity Burden in Automated Segmentation Distinguishes Late-Life Depressed Subjects From Comparison Subjects Matched for Vascular Risk Factors 
The American journal of psychiatry  2008;165(4):524-532.
Objective
Segmented brain white matter hyperintensities were compared between subjects with late-life depression and age-matched subjects with similar vascular risk factor scores. Correlations between neuropsychological performance and whole brain-segmented white matter hyperintensities and white and gray matter volumes were also examined.
Method
Eighty-three subjects with late-life depression and 32 comparison subjects underwent physical examination, psychiatric evaluation, neuropsychological testing, vascular risk factor assessment, and brain magnetic resonance imaging (MRI). Automated segmentation methods were used to compare the total brain and regional white matter hyperintensity burden between depressed patients and comparison subjects.
Results
Depressed patients and comparison subjects did not differ in demographic variables, including vascular risk factor, or whole brain-segmented volumes. However, depressed subjects had seven regions of greater white matter hyperintensities located in the following white matter tracts: the superior longitudinal fasciculus, fronto-occipital fasciculus, uncinate fasciculus, extreme capsule, and inferior longitudinal fasciculus. These white matter tracts underlie brain regions associated with cognitive and emotional function. In depressed patients but not comparison subjects, volumes of three of these regions correlated with executive function; whole brain white matter hyperintensities correlated with executive function; whole brain white matter correlated with episodic memory, processing speed, and executive function; and whole brain gray matter correlated with processing speed.
Conclusions
These findings support the hypothesis that the strategic location of white matter hyperintensities may be critical in late-life depression. Further, the correlation of neuropsychological deficits with the volumes of whole brain white matter hyperintensities and gray and white matter in depressed subjects but not comparison subjects supports the hypothesis of an interaction between these structural brain components and depressed status.
doi:10.1176/appi.ajp.2007.07010175
PMCID: PMC4118770  PMID: 18281408
8.  Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression 
Journal of affective disorders  2008;112(1-3):206-211.
Background
Major depression (MDD) is characterized by altered emotion processing and deficits in cognitive control. In cognitive interference tasks, patients with MDD have shown excessive amygdala activity and under-recruitment of dorsolateral prefrontal cortex (DLPFC). The purpose of this study was to examine the effects of antidepressant treatment on anomalous neural activity in cognitive-control and emotion-processing circuitry.
Methods
Functional magnetic resonance imaging was conducted on depressed patients (n=23) (both before and after antidepressant treatment) compared with matched controls (n= 18) while they performed a cognitive task involving attended and unattended fear-related stimuli.
Results
After eight weeks of SSRI antidepressant treatment, patients with depression showed significantly increased DLPFC activity to unattended fear-related stimuli and no longer differed from controls in either DLPFC or amygdala activity.
Conclusions
These results suggest that antidepressant treatment increases DLPFC under-activity during cognitive tasks that include emotional interference.
Limitations
The sample was fairly homogeneous and this may limit generalizability.
doi:10.1016/j.jad.2008.04.027
PMCID: PMC2825146  PMID: 18559283
9.  Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression 
Biological psychiatry  2007;63(4):377-384.
Background
Major depression is characterized by a negativity bias: an enhanced responsiveness to, and memory for, affectively negative stimuli. However it is not yet clear whether this bias represents (1) impaired top-down cognitive control over affective responses, potentially linked to deficits in dorsolateral prefrontal cortex function; or (2) enhanced bottom-up responses to affectively-laden stimuli that dysregulate cognitive control mechanisms, potentially linked to deficits in amygdala and anterior cingulate function.
Methods
We used an attentional interference task using emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control circuitry and emotion-processing circuitry. A total of 27 patients with major depression and 24 controls were tested. Event-related functional magnetic resonance imaging was carried out as participants directly attended to, or attempted to ignore, fear-related stimuli.
Results
Compared to controls, patients with depression showed an enhanced amygdala response to unattended fear-related stimuli (relative to unattended neutral). By contrast, control participants showed increased activity in right dorsolateral prefrontal cortex (Brodmann areas 46/9) when ignoring fear stimuli (relative to neutral), which the patients with depression did not. In addition, the depressed participants failed to show evidence of error-related cognitive adjustments (increased activity in bilateral dorsolateral prefrontal cortex on post-error trials), but the control group did show them.
Conclusions
These results suggest multiple sources of dysregulation in emotional and cognitive control circuitry in depression, implicating both top-down and bottom-up dysfunction.
doi:10.1016/j.biopsych.2007.06.012
PMCID: PMC2268639  PMID: 17719567
10.  Treatment Course With Antidepressant Therapy in Late-Life Depression 
The American journal of psychiatry  2012;169(11):1185-1193.
Objective
In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial.
Method
In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antide-pressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time.
Results
Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyperintensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not.
Conclusions
These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response.
PMCID: PMC3752387  PMID: 23534057
11.  Biological Basis of Late Life Depression 
Current psychiatry reports  2012;14(4):273-279.
Late life depression (LLD) is an important area of research given the growing elderly population. The purpose of this review is to examine the available evidence for the biological basis of LLD. Structural neuroimaging shows specific gray matter structural changes in LLD as well as ischemic lesion burden via white matter hyperintensities. Similarly, specific neuropsychological deficits have been found in LLD. An inflammatory response is another possible underlying contributor to the pathophysiology of LLD. We review the available literature examining these multiple facets of LLD and how each may affect clinical outcome in the depressed elderly.
doi:10.1007/s11920-012-0279-6
PMCID: PMC3752388  PMID: 22562412
Late life depression; LLD; Elderly; Ischemic lesion burden; White matter hyperintensities; Neuropsychological factors; Cognitive deficits; Inflammatory markers; Treatment outcome; Structural neuroimaging
12.  Cognitive Improvement Following Treatment in Late Life Depression: Relationship to Vascular Risk and Age of Onset 
Objectives
To test the hypothesis that the degree vascular burden and/or age of onset may influence the degree to which cognition can improve during the course of treatment in late life depression.
Design
Measurement of cognition both prior to and following 12-weeks of treatment with Sertraline.
Setting
University Medical Centers (Washington University and Duke University)
Participants
166 individuals with late life depression.
Intervention
Sertraline treatment.
Measurements
The cognitive tasks were grouped into five domains (language, processing speed, working memory, episodic memory, and executive function). We measured vascular risk using the Framingham Stroke Risk Profile measure. We measured T2 based white matter hyperintensities using the Fazekas criteria.
Results
Both episodic memory and executive function demonstrated significant improvement among adults with late life depression during treatment with sertraline. Importantly, older age, higher vascular risk scores, and lower baseline Mini-Mental state exam scores predicted less change in working memory. Further, older age, later age of onset, and higher vascular risk scores predicted less change in executive function.
Conclusions
These results have important clinical implications, in that they suggest that a regular assessment of vascular risk in older adults with depression is necessary as a component of treatment planning and in predicting prognosis, both for the course of the depression itself and for the cognitive impairments that often accompany depression in later life.
doi:10.1097/JGP.0b013e318246b6cb
PMCID: PMC3382028  PMID: 22430020
Cognition; Vascular Depression; Treatment; white matter
13.  Pretreatment cerebral metabolic activity correlates with antidepressant efficacy of vagus nerve stimulation in treatment-resistant major depression: a potential marker for response? 
Journal of affective disorders  2012;139(3):283-290.
Background
Pretreatment brain activity in major depressive disorder correlates with response to antidepressant therapies, including pharmacotherapies and transcranial magnetic stimulation. The purpose of this trial was to examine whether pretreatment regional metabolic activity in selected regions of interest (ROIs) predicts antidepressant response following 12 months of vagus nerve stimulation (VNS) in 15 patients with treatment-resistant major depression (TRMD).
Methods
Fluorodeoxyglucose positron emission tomography (FDG PET) was used to assess regional mean relative cerebral metabolic rate for glucose (CMRGlu) in four ROIs (anterior insular, orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices) at baseline (prior to VNS activation). Depression severity was assessed at baseline and after 12 months of VNS using the Hamilton Depression Rating Scale (HDRS), with response defined as ≥50% reduction in HDRS from baseline.
Results
Baseline CMRGlu in the anterior insular cortex differentiated VNS responders (n = 11) from nonresponders (n = 4) and correlated with HDRS change (r = .64, p = .01). In a regression analysis, lower anterior insular cortex CMRGlu (p = .004) and higher orbitofrontal cortex CMRGlu (p = .047) together predicted HDRS change (R2 = .58, p = .005). In a whole brain, voxel-wise analysis, baseline CMRGlu in the right anterior insular cortex correlated with HDRS change (r = .78, p = .001).
Limitations
Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled.
Conclusions
This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.
doi:10.1016/j.jad.2012.02.007
PMCID: PMC3598572  PMID: 22397889
Vagus nerve stimulation; Depression; Positron emission tomography; Treatment-resistant depression; Fluorodeoxyglucose PET; Treatment response
14.  Brain Blood-flow Change with Acute Vagus Nerve Stimulation in Treatment-Refractory Major Depressive Disorder 
Brain Stimulation  2011;5(2):163-171.
Background
Existing neuroimaging studies of vagus nerve stimulation (VNS) in treatment resistant major depression (TRMD) suggest that many brain regions (e.g., prefrontal cortex, thalamus, cingulate cortex, insular cortex) associated with mood disorders undergo alterations in blood flow/metabolism.
Objective/Hypothesis
Positron emission tomography (PET oxygen-15 labeled water or PET [15O] H2O) was used to identify changes in regional cerebral blood flow (rCBF) in response to immediate VNS in 13 subjects with TRMD. We hypothesized rCBF changes along the afferent pathway of the vagus and in regions associated with depression (e.g., orbitofrontal cortex, amygdala, insular cortex).
Methods
Six 90-second PET [15O] H2O scans were performed on 13 subjects in a VNS off-on sequence. Following normalization for global uptake and realignment to standard atlas space, statistical t-images (p < 0.005) were used to evaluate rCBF change.
Results
VNS induced significant rCBF decreases in the left and right lateral orbitofrontal cortex and left inferior temporal lobe. Significant increases were found in the right dorsal anterior cingulate, left posterior limb of the internal capsule/medial putamen, the right superior temporal gyrus, and the left cerebellar body. Post-hoc analysis found small to moderate correlations between baseline acute change in rCBF and antidepressant response following 12 months of VNS.
Conclusions
Regions undergoing rCBF change in response to acute VNS are consistent with the known afferent pathway of the vagus nerve and models of brain network in depression. Larger studies assessing the correlation between acute stimulation patterns and antidepressant outcomes with VNS are needed.
doi:10.1016/j.brs.2011.03.001
PMCID: PMC3270206  PMID: 22037127
Vagus nerve stimulation; Depression; Positron emission tomography; Regional blood flow; Treatment-resistant depression
15.  Childhood adversity predicts earlier onset of Major Depression but not reduced hippocampal volume 
Psychiatry research  2008;162(1):39-49.
Childhood adversity may influence severity and age of onset of depression, potentially mediated by greater vulnerability to an existing biochemical or neural mechanism. Prior studies have suggested that reduced hippocampal volume is a result of childhood adversity. This study examined the relationship between childhood adversity, hippocampal volumes and clinical characteristics in women who were recruited for depression history rather than abuse experiences. Thirty-one women with remitted unipolar depression and 24 psychiatrically healthy women completed the Childhood Experience of Care and Abuse (Bifulco et al 1994). High resolution MRI scans and hippocampal volumetric determination by stereological assessment were obtained. We found that childhood adversity was associated with a history of recurrent depression and with earlier age of depression onset. We did not find a relationship between childhood adversity and hippocampal volumes in this sample with mild childhood adversity. Our results suggest that the decreased hippocampal volume seen in Major Depressive Disorder may be mediated by additional factors. Further research is needed to more fully understand the interrelationships among childhood adversity, hippocampal morphology, neuroendocrine regulation, and other genetic and environmental factors influencing vulnerability to depression.
doi:10.1016/j.pscychresns.2007.04.004
PMCID: PMC3588158  PMID: 18068956
Magnetic resonance imaging; depression; abuse; CECA
16.  Altered emotional interference processing in the amygdala and insula in women with Post-Traumatic Stress Disorder☆☆☆ 
NeuroImage : Clinical  2012;2:43-49.
Background
Post-Traumatic Stress Disorder (PTSD) is characterized by distinct behavioral and physiological changes. Given the significant impairments related to PTSD, examination of the biological underpinnings is crucial to the development of theoretical models and improved treatments of PTSD.
Methods
We used an attentional interference task using emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control circuitry and emotion-processing circuitry. A total of 32 women with PTSD (based on an interpersonal trauma) and 21 matched controls were tested. Event-related functional magnetic resonance imaging was carried out as participants directly attended to, or attempted to ignore, fear-related stimuli.
Results
Compared to controls, patients with PTSD showed hyperactivity in several brain regions, including the amygdala, insula, as well as dorsal lateral and ventral PFC regions.
Conclusions
These results are consistent with previous studies that have higher amygdala and insular activation in PTSD subjects. However, inhibition of suppression of PFC regions is inconsistent with the fear circuitry model hypothesized by prior research. We suggest that the specific emotional conflict task used appears to target implicit or automatic emotional regulation instead of explicit or effortful emotional regulation. This is particularly relevant as it posited that emotional regulatory difficulties in anxiety disorders such as PTSD appear to occur in implicit forms of emotion regulation.
Highlights
► We use an emotional interference task to examine brain activity in women with PTSD. ► Significant hyperactivity was found in amygdala and insula in PTSD subjects. ► Hyperactivity in PFC regions were inconsistent with the fear circuitry hypothesis. ► Findings suggest PTSD subjects fail to normally down-regulate activity in the DMN.
doi:10.1016/j.nicl.2012.11.003
PMCID: PMC3777837  PMID: 24179757
PTSD; fMRI; Trauma; Amygdala; Insula; Default mode network
17.  Amyloid-Beta Plaque Growth in Cognitively Normal Adults: Longitudinal PIB Data 
Annals of neurology  2011;70(5):857-861.
Amyloid-beta (Aβ) accumulation was evaluated with two PIB PET scans about 2.5 years apart in 146 cognitively normal adults. Seventeen of 21 participants with initially elevated Aβ deposition demonstrated subsequent Aβ plaque growth (approximately 8.0% per year) and none reverted to a state of no Aβ deposits. Ten individuals converted from negative to positive PIB status, based on a threshold of the mean cortical binding potential, representing a conversion rate of 3.1% per year. Individuals with an ε4 allele of apolipoprotein E demonstrated increased incidence of conversion (7.0% per year). Our findings suggest that the major growth in Aβ burden occurs during a preclinical stage of AD, prior to the onset of AD-related symptoms.
doi:10.1002/ana.22608
PMCID: PMC3243969  PMID: 22162065
preclinical Alzheimer disease; amyloid-beta accumulation; apolipoprotein E; positron emission tomography; [11C]PIB
18.  A Generalized Estimating Equations Approach for Resting-State Functional MRI Group Analysis 
An Alzheimer’s fMRI study has motivated us to evaluate inter-regional correlations between groups. The overall objective is to assess inter-regional correlations at a resting-state with no stimulus or task. We propose using a generalized estimating equation (GEE) transition model and a GEE marginal model to model the within-subject correlation for each region. Residuals calculated from the GEE models are used to correlate brain regions and assess between group differences. The standard pooling approach of group averages of the Fisher-z transformation assuming temporal independence is a typical approach used to compare group correlations. The GEE approaches and standard Fisher-z pooling approach are demonstrated with an Alzheimer’s disease (AD) connectivity study in a population of AD subjects and healthy control subjects. We also compare these methods using simulation studies and show that the transition model may have better statistical properties.
doi:10.1109/IEMBS.2011.6091254
PMCID: PMC3433165  PMID: 22255477
19.  Outcomes of National Career Development Program that Promotes the Transition to Independent Scientist 
Academic Medicine  2011;86(9):1179-1184.
Purpose
The loss of new investigators from academic science is a “crisis” placing the future of biomedical science at risk. Failure to obtain independent funding contributes significantly to attrition from the NIH career path. The purpose of this paper is to describe the components and outcomes of the Advanced Research Institute (ARI) in Geriatric Mental Health, an NIMH grant-funded national program that targets successful transition of new investigators to independence.
Method
The authors first describe the program participants and key components. They then compare the record of federal grant funding, derived from the NIH Reporter database, of the first four cohorts (2004–2007; n=42) to those of all NIMH mentored career development (K) awardees funded 2001–2005 (n=404).
Results
As of January 2010, 45.2% of Scholars had achieved R01 funding. Nearly 70% obtained some NIH grant (not including K or small grants). Among all NIMH mentored K awardees, ARI Scholars were 2.36 (p=0.048) more likely to achieve an R01; outcomes were similar (OR=2.42, p= .045) when including R34s.
Conclusions
Based on objective outcomes, the Advanced Research Institute (ARI) in Geriatric Mental Health offers an effective model to promoting successful transition of new investigators to independence. While organized around a specific public health and scientific need, ARI’s components are generalizable to other fields. Further, the inclusion of biological, clinical and services researchers into a single program promotes translational science. Thus ARI is one tool to stemming attrition from the NIH career path and promoting the next generation of science.
doi:10.1097/ACM.0b013e3182254399
PMCID: PMC3162100  PMID: 21785315
20.  One-Year Change in Anterior Cingulate Cortex White Matter Microstructure: Relationship with Late-Life Depression Outcomes 
Objectives
Differences in white matter structure measured with diffusion tensor imaging (DTI) are associated with late-life depression, but results examining how these differences relate to antidepressant remission are mixed. To better describe these relationships, we examined how one-year change in DTI measures are related to one-year course of depression.
Design
One-year cross-sectional follow-up to a 12-week clinical trial of sertraline.
Setting
Outpatients at an academic medical center.
Participants
29 depressed and 20 never-depressed elderly subjects. Over the one-year period, 16 depressed subjects achieved and maintained remission, while 13 did not.
Measurements
One-year change in fractional anisotropy (FA) and diffusivity in frontal white matter, as measured by DTI.
Results
Contrary to our hypotheses, depressed subjects who did not remit over the study interval exhibited significantly less change in anterior cingulate cortex white matter FA than did never-depressed or depressed-remitted subjects. There were no group differences in other frontal or central white matter regions. Moreover, there was a significant positive relationship between change in MADRS and change in anterior cingulate cortex FA, wherein greater interval decline in FA was associated with greater interval decline in MADRS.
Conclusions
Older depressed individuals who remit exhibit white matter changes comparable to what is observed in never-depressed individuals, while nonremitters exhibit significantly less change in anterior cingulate cortex FA. Such a finding may be related to either antidepressant effects on brain structure or the effects of chronic stress on brain structure. Further work is needed to better understand this relationship.
doi:10.1097/JGP.0b013e3181e70cec
PMCID: PMC3000437  PMID: 20808126
Aging; depression; frontal lobe; anterior cingulate cortex; white matter; diffusion tensor imaging
21.  APOE4 Allele Disrupts Resting State fMRI Connectivity in the Absence of Amyloid Plaques or Decreased CSF Aβ42 
Identifying high risk populations is an important component of disease prevention strategies. One approach is examining neuroimaging parameters that differ in Alzheimer’s disease (AD), including functional connections known to be disrupted within the “default mode network” (DMN). We have previously shown these same disruptions in cognitively normal elderly, who have amyloid-beta (Aβ) plaques detected using PIB PET imaging, suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI ) in participants without preclinical fibrillar amyloid deposition (PIB−). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB− were categorized into those with and without an APOE 4 allele and studied using fcMRI. APOE 4 allele carriers (E4+) differed significantly from E4− in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed prior to any manifestations of cognitive changes and in the absence of brain fibrillar amyloid-beta (Aβ) plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.
doi:10.1523/JNEUROSCI.3987-10.2010
PMCID: PMC3023180  PMID: 21159973
PIB; fMRI; amyloid; Alzheimer’s disease; resting state; precuneus; hippocampus; APOE4
22.  Amyloid Plaques Disrupt Resting State Default Mode Network Connectivity in Cognitively Normal Elderly 
Biological psychiatry  2009;67(6):584-587.
Background
Important functional connections within the “default mode network” (DMN) are disrupted in Alzheimer’s disease (AD), likely from amyloid-beta (Aβ) plaque-associated neuronal toxicity. Here we sought to determine if pathological effects of Aβ amyloid plaques could be seen even in the absence of a task by examining functional connectivity in cognitively normal participants with and without preclinical amyloid deposition.
Methods
Participants with Alzheimer’s disease (AD) (n= 35) were compared with 68 cognitively normal participants who were further subdivided by PET PIB imaging into those without evidence of brain amyloid (PIB−) and those with brain amyloid (PIB+) deposition.
Results
Resting state fMRI demonstrated that, compared with the PIB− group, the PIB+ group differed significantly in functional connectivity of the precuneus to hippocampus, parahippocampus, anterior cingulate, dorsal cingulate, gyrus rectus, superior precuneus and visual cortex. These differences were in the same regions, and in the same direction, as differences found in the AD group.
Conclusions
Thus, prior to any manifestations of cognitive or behavioral changes there were differences in resting state connectivity in cognitively normal subjects with brain amyloid deposition, suggesting that early manifestation of Aβ toxicity can be detected using resting state fMRI.
doi:10.1016/j.biopsych.2009.08.024
PMCID: PMC2829379  PMID: 19833321
PIB; fMRI; amyloid; Alzheimers Disease; resting state; precuneus; hippocampus
23.  Evaluation of 5-ethynyl-2′-deoxyuridine staining as a sensitive and reliable method for studying cell proliferation in the adult nervous system 
Brain research  2010;1319C:21-32.
Recently, a novel method for detection of DNA synthesis has been developed based on the incorporation of 5–ethynyl–2′–deoxyuridine (EdU), a thymidine analogue, into cellular DNA and the subsequent reaction of EdU with a fluorescent azide in a copper–catalyzed [3+2] cycloaddition (“Click” reaction). In the present study, we evaluated this method for studying cell proliferation in the adult central nervous system in comparison with the “gold standard” method of 5–bromo–2′–deoxyuridine (BrdU) staining using two behavioral paradigms, voluntary exercise and restraint stress. Our data demonstrate that the number of EdU positive cells in the dentate gyrus of the hippocampus (DG) slightly increased in an EdU dose–dependent manner in both the control and voluntary exercise (running) mouse groups. The number of EdU–labeled cells was comparable to the number of BrdU–labeled cells in both the control and running mice. Furthermore, EdU and BrdU co–localized to the same cells within the DG. Voluntary exercise significantly increased the number of EdU and BrdU positive cells in the DG. In contrast, restraint stress significantly decreased the number of EdU positive cells. The EdU positive cells differentiated into mature neurons. EdU staining is compatible with immunohistochemical staining of other antigens. Moreover, our data demonstrated EdU staining can be combined with BrdU staining, providing a valuable tool of double labeling DNA synthesis, e.g., for tracking the two populations of neurons generated at different time points. In conclusion, our results suggest that EdU staining is a fast, sensitive and reproducible method to study cell proliferation in the central nervous system.
doi:10.1016/j.brainres.2009.12.092
PMCID: PMC2826567  PMID: 20064490
5–ethynyl–2′–deoxyuridine; 5–bromo–2′–deoxyuridine; BrdU; adult neurogenesis; hippocampus
24.  Support for the Vascular Depression Hypothesis in Late Life Depression: Results from a Two Site Prospective Antidepressant Treatment Trial 
Archives of general psychiatry  2010;67(3):277-285.
Context
Research on “vascular depression” has used two approaches to subtype late life depression (LLD) based on executive dysfunction or white matter hyperintensity (WMH) severity.
Objective
Evaluate the relationship of neuropsychological performance and WMH to clinical response in LLD.
Design
2-site prospective nonrandomized controlled trial.
Setting
Outpatient clinics at Washington University and Duke University.
Participants
217 subjects age ≥ 60 met DSM-IV criteria for major depression, scored ≥ 20 (MADRS), received vascular risk factor (VRF) scores, neuropsychological testing and MRI scan; were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade WMH lesions.
Intervention
12 weeks of sertraline treatment, titrated by clinical response.
Outcome
Montgomery-Asberg Depression Rating Scale (MADRS) score over time.
Results
Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (p = 0.002); language (p = 0.007); working memory (p = 0.01); processing speed (p = 0.0001); executive function factor scores (p = 0.002), and categorical Fazekas ratings (p = 0.049) predicted MADRS scores, controlling for age, education, age of onset and race. Controlling for baseline MADRS scores these factors remained significant predictors of decrease in MADRS scores except working memory and Fazekas ratings. 33% of subjects achieved remission (MADRS ≤ 7). Remitters differed from non-remitters in baseline cognitive processing speed, executive function, language, episodic memory and VRF scores.
Discussion
Comprehensive neuropsychological function and WMH severity predicted MADRS scores prospectively over a 12 week SSRI treatment course in LLD. Baseline neuropsychological function differentiated remitters from non-remitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with VRF severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity.
doi:10.1001/archgenpsychiatry.2009.204
PMCID: PMC2838210  PMID: 20194828
late life depression; antidepressant; neuropsychology; WMH; cognitive deficit; age of onset; vascular risk factors; factor scores
25.  DIFFUSE MICROSTRUCTURAL ABNORMALITIES OF NORMAL APPEARING WHITE MATTER IN LATE LIFE DEPRESSION: A DIFFUSION TENSOR IMAGING STUDY 
Biological psychiatry  2009;66(3):245-252.
Many recent studies have identified white matter abnormalities in late life depression (LLD). These abnormalities include an increased volume of discrete white matter lesions (hyperintensities on T2-weighted imaging) and changes in the diffusion tensor properties of water. However, no study of LLD to date has examined the integrity of white matter outside of discrete lesions, i.e., in normal appearing white matter. We performed T1- and T2-weighted imaging as well as diffusion tensor imaging (DTI) in depressed elderly subjects (n=73) and non-depressed control subjects (n=23) matched for age and cerebrovascular risk factors. The structural images were segmented into white matter, gray matter, cerebrospinal fluid and discrete white matter lesions. DTI parameters were calculated in white matter regions of interest after excluding the white matter lesions. Widespread LLD vs. control group differences were found, particularly in prefrontal regions, where the DTI abnormalities correlated with cognitive processing speed. These results suggest that further investigation is warranted to determine the basic pathophysiology and potential reversibility of LLD.
doi:10.1016/j.biopsych.2009.02.032
PMCID: PMC2804471  PMID: 19375071
Depression; MRI; Diffusion Tensor Imaging; Geriatrics; segmentation; LLD

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