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author:("mintue, Mark")
1.  Development of a PET Radiotracer for Noninvasive Imaging of the Reactive Oxygen Species, Superoxide, in vivo 
Organic & biomolecular chemistry  2014;12(25):4421-4431.
Reactive oxygen species (ROS) have been implicated in the pathogenesis of a wide range of human disease states and drug toxicities, but development of imaging tools to study ROS biology in vivo remains a challenge. Here we synthesized and validated a novel PET tracer (12) and its 18F radiolabeled version [18F]12 to allow PET (positron emission tomography) imaging of superoxide in vivo. Initial analysis of ROS reaction kinetics found that compound 12 was rapidly and selectively oxidized by superoxide, but not other ROS. Cell culture studies in EMT6 cells exposed to the cancer chemotherapeutic agent Doxorubicin (DOX), which activates the superoxide-generating enzyme, NADPH oxidase, showed that compound 12 was a sensitive and specific probe for superoxide in cells. The microPET imaging of heart in mice with DOX-induced cardiac inflammation observed 2-fold greater oxidation of [18F]12 in the DOX-treated mice compared to controls (p=0.02), the results were confirmed by distribution studies on organs subsequently removed from the mice and HPLC analysis of [18F] radioactivity compounds. These data indicate that compound 12 is a useful PET tracer to imaging ROS in vivo.
PMCID: PMC4122299  PMID: 24847866
ethidium; dihydroethidium; reactive oxygen species; superoxide; PET imaging
2.  Severe hippocampal atrophy is not associated with depression in temporal lobe epilepsy 
Depression in temporal lobe epilepsy (TLE) is common, is a strong predictor of subjective disability, and may have unique pathophysiological characteristics. Previous studies showed that reduced hippocampal volume is associated with significant depressive symptoms in TLE patients. We utilized regions of interest analysis of high-resolution brain MRI and a reliable and valid measure of depressive symptoms to evaluate 28 consecutive adult subjects with video/EEG confirmed TLE. Regions of interest were based on prior human and animal studies of mood and behavioral dysfunction. Forty-three percent of the entire group had significant symptoms of depression, defined by a Beck Depression Inventory (BDI) score of greater than 15. Total hippocampal volumes were significantly smaller in the group with BDI< 15, (p< 0.007). None of the subjects in the quartile with the smallest left hippocampal volume had a BDI score greater than 15, compared to 57% of the subjects in the upper three quartiles (p< 0.008). No other limbic brain structures that we assessed: amygdala, subcallosal gyrus, subgenual gyrus, gyrus rectus, or total cerebral volume, were associated with depressive symptoms. Adequate hippocampal integrity may be necessary to maintain depression symptoms in mesial temporal lobe epilepsy. This finding also supports the possibility of a unique mechanism for depression in mesial temporal lobe epilepsy, such as hyerexcitable neuronal influence on the limbic network.
PMCID: PMC4009341  PMID: 24667480
hippocampus; depression; temporal lobe epilepsy; quantitative MRI; Beck Depression Inventory
3.  Antidepressant response to aripiprazole augmentation associated with enhanced FDOPA utilization in striatum: a preliminary PET study 
Psychiatry research  2014;221(3):231-239.
Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole’s antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[18F]-fluoro-3,4-dihydroxy-L-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; eleven responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity.
PMCID: PMC3982608  PMID: 24468015
Aripiprazole; treatment-resistant depression; Positron emission tomography; Dopamine; Caudate
4.  Levodopa effects on [ 11C]raclopride binding in the resting human brain 
F1000Research  2015;4:23.
Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [ 11C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS).
Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS.
Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BP ND) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BP ND voxel by voxel over the entire brain.
Results: DA release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa’s effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects.
Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa.
PMCID: PMC4490799  PMID: 26180632
dopamine; D2; receptor; raclopride; positron; emission; tomography; PET; levodopa; dopamine; Tourette; syndrome; nucleus; accumbens; substantia; nigra; midbrain
5.  Neuropathologic Heterogeneity Does Not Impair Florbetapir-PET Postmortem Correlates 
Neuropathologic heterogeneity is often present within Alzheimer’s disease (AD). We sought to determine if amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinicopathologically-defined AD and 17 non-demented cases (ND) with quantitative florbetapir F-18 (18F-AV-45) PET imaging during life and histological β-amyloid quantification and neuropathologic examination were assessed. AD cases were divided on the basis of concurrent pathologies, including those with Lewy bodies (N=21), white matter rarefaction (N=27), severe cerebral amyloid angiopathy (N=11), argyrophilic grains (N=5) and TDP-43 inclusions (N=18). Many cases exhibited more than one type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in six cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p values <0.001). All AD subgroups had significantly greater amyloid measures compared to ND, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with Lewy bodies had significantly decreased SUVr measures compared to AD cases without (p = 0.002); there were no other paired comparison differences. These findings indicate florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
PMCID: PMC4037918  PMID: 24335535
argyrophilic grains; autopsy; cerebral amyloid angiopathy; Lewy bodies; plaques; TDP-43; vascular dementia; white matter; leuko-araiosis
6.  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.
PMCID: PMC4269372  PMID: 24828079
7.  Comparing PET imaging and CSF measurements of Aβ 
Annals of neurology  2013;74(6):826-836.
We examined agreement and disagreement between two biomarkers of Aβ deposition (amyloid PET and CSF Aβ1-42) in normal aging and dementia in a large multicenter study.
Concurrently acquired florbetapir-PET and CSF Aβ were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) participants (N=374) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We also compared Aβ measurements in a separate group with serial CSF measurements over 3.1 +/− 0.8 yrs that preceded a single florbetapir session. Additional biomarker and cognitive data allowed us to further examine profiles of discordant cases.
Florbetapir and CSF Aβ were inversely correlated across all diagnostic groups, and dichotomous measurements were in agreement in 86% of subjects. Among subjects showing the most disagreement, the two discordant groups had different profiles: the florbetapir+/CSF Aβ− group was larger (N=13) and was made up of only normal and early MCI subjects; while the florbetapir−/CSF Aβ+ group was smaller (N=7), had poorer cognitive function and higher CSF tau, but no ApoE4 carriers. In the longitudinal sample, we observed both stable longitudinal CSF Aβ trajectories and those actively transitioning from normal to abnormal, but the final CSF Aβ measurements were in good agreement with florbetapir cortical retention.
CSF and amyloid-PET measurements of Aβ were consistent in the majority of subjects in the cross-sectional and longitudinal populations. Based on our analysis of discordant subjects, the available evidence did not show that CSF Aβ regularly becomes abnormal prior to fibrillar Aβ accumulation early in the course of disease.
PMCID: PMC3748164  PMID: 23536396
8.  Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions 
Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease (AD) pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation and dysphasia. Positron emission tomography (PET) imaging using the amyloid ligand 18F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the cerebral cortex, thalamus and striatum, Braak stage II neurofibrillary degeneration and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that AD is the sole cause.
PMCID: PMC4167919  PMID: 24927705
Alzheimer's disease; frontotemporal dementia; neurofibrillary degeneration; neuritic amyloid plaques
9.  Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression 
Brain stimulation  2013;6(5):788-797.
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.
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.
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.
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.
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.
PMCID: PMC3954813  PMID: 23485649
Treatment resistant depression; Vagus nerve stimulation; Positron emission tomography; Depression; Antidepressant
10.  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.
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.
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.
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.
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.
PMCID: PMC4118770  PMID: 18281408
11.  Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later 
Neurology  2013;80(19):1784-1791.
We compared the ability of molecular biomarkers for Alzheimer disease (AD), including amyloid imaging and CSF biomarkers (Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42), to predict time to incident cognitive impairment among cognitively normal adults aged 45 to 88 years and followed for up to 7.5 years.
Longitudinal data from Knight Alzheimer's Disease Research Center participants (N = 201) followed for a mean of 3.70 years (SD = 1.46 years) were used. Participants with amyloid imaging and CSF collection within 1 year of a clinical assessment indicating normal cognition were eligible. Cox proportional hazards models tested whether the individual biomarkers were related to time to incident cognitive impairment. “Expanded” models were developed using the biomarkers and participant demographic variables. The predictive values of the models were compared.
Abnormal levels of all biomarkers were associated with faster time to cognitive impairment, and some participants with abnormal biomarker levels remained cognitively normal for up to 6.6 years. No differences in predictive value were found between the individual biomarkers (p > 0.074), nor did we find differences between the expanded biomarker models (p > 0.312). Each expanded model better predicted incident cognitive impairment than the model containing the biomarker alone (p < 0.005).
Our results indicate that all AD biomarkers studied here predicted incident cognitive impairment, and support the hypothesis that biomarkers signal underlying AD pathology at least several years before the appearance of dementia symptoms.
PMCID: PMC3719431  PMID: 23576620
12.  PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer’s disease and Lewy body disorders 
BMC Neurology  2014;14:79.
Biomarkers based on the underlying pathology of Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson’s disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2).
Patients with DLB and AD, Parkinson’s disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism.
11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011).
The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients ( identifier: NCT00857506, registered March 5, 2009).
PMCID: PMC4027995  PMID: 24716655
PET imaging; Alzheimer’s disease; Parkinson’s disease; Biomarkers
13.  Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals 
Neurobiology of aging  2012;34(3):822-831.
The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 (18F-AV-45) amyloid PET, and cognition in healthy older control subjects (HC). Seventy-eight HC subjects were assessed with a brief cognitive test battery and PET imaging with florbetapir F 18. A standard uptake value ratio (SUVr) was computed for mean data from six cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive (Aβ+) or amyloid negative (Aβ−) by three readers. Higher SUVr correlated with lower immediate memory (r=−0.33; p=0.003) and delayed recall scores (r=−0.25; p=0.027). Performance on immediate recall was also lower in the visually rated Aβ+ compared to Aβ− HC (p=0.04), with a similar trend observed in delayed recall (p=0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether florbetapir F 18 may also predict subsequent cognitive decline.
PMCID: PMC3518678  PMID: 22878163
14.  Radiation dosimetry of florbetapir F 18 
EJNMMI Research  2014;4:4.
Florbetapir is one of several 18F-labeled amyloid plaque imaging tracers for positron emission tomography (PET). As the bio-distribution and radiation dose of PET tracers in human research are important for estimating the relative risks and benefits, a study was conducted to obtain this information on florbetapir.
Nine cognitively normal subjects (six females and three males, age 58 ± 10 years, weight 81 ± 17 kg) received an intravenous bolus injection of 395 ± 27.9 MBq of florbetapir, and whole-body emission scans were performed over approximately 6 h. Computed tomography scans were acquired for attenuation correction. Volumes of interest (VOIs) for source organs including the brain, liver, lung, heart wall, and vertebrae were defined on the PET images. The VOIs of the gallbladder, urinary bladder, and large and small intestines were also defined. Using reference man organ volumes (ICRP 30), total activity was calculated per organ for each time point. The resultant time-activity curves (TACs) were fitted with constrained exponentials. Kinetic data were entered into OLINDA/EXM software to calculate dose estimates; the dynamic urinary bladder and ICRP 30 GI tract models were employed. The effective dose (ED) for each subject was estimated from the acquired data using the adult model.
The mean ED determined for nine healthy volunteers was 18.60 ± 4.26 μSv/MBq or 6.88 mSv for a 370-MBq dose. The organs that received the highest radiation absorbed doses were the gallbladder, upper large intestine, small intestine, liver, and urinary bladder at 143.0 ± 80.20, 74.50 ± 34.20, 65.50 ± 29.60, 64.40 ± 22.10, and 27.10 ± 11.70 μSv/MBq, respectively.
The ED for florbetapir has been calculated for nine healthy volunteers. At a dose of 370 MBq florbetapir, the total average ED is approximately 6.88 mSv.
PMCID: PMC4061749  PMID: 24401181
15.  Noninvasive estimation of the arterial input function in positron emission tomography imaging of cerebral blood flow 
Positron emission tomography (PET) with 15O-labeled water can provide reliable measurement of cerebral blood flow (CBF). Quantification of CBF requires knowledge of the arterial input function (AIF), which is usually provided by arterial blood sampling. However, arterial sampling is invasive. Moreover, the blood generally is sampled at the wrist, which does not perfectly represent the AIF of the brain, because of the effects of delay and dispersion. We developed and validated a new noninvasive method to obtain the AIF directly by PET imaging of the internal carotid artery in a region of interest (ROI) defined by coregistered high-resolution magnetic resonance angiography. An ROI centered at the petrous portion of the internal carotid artery was defined, and the AIF was estimated simultaneously with whole brain blood flow. The image-derived AIF (IDAIF) method was validated against conventional arterial sampling. The IDAIF generated highly reproducible CBF estimations, generally in good agreement with the conventional technique.
PMCID: PMC3597366  PMID: 23072748
arterial input function; PET
16.  Quantitative Analysis of PiB-PET with FreeSurfer ROIs 
PLoS ONE  2013;8(11):e73377.
In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.
PMCID: PMC3819320  PMID: 24223109
17.  Amyloid-β Dynamics in Human Plasma 
Archives of neurology  2012;69(12):10.1001/archneurol.2012.18107.
A marked decrease of Aβ42 in the cerebrospinal fluid (CSF) of patients with incipient Alzheimer's Disease (AD) has been well documented. However, contradictory results have been reported from studies on plasma Aβ levels as diagnostic markers for AD.
To investigate dynamic changes in human plasma Aβ levels, evaluate the effects of aging and amyloidosis on these dynamics, and determine their correlation with CSF Aβ levels.
Design, Settings, and Participants
This was a repeated plasma and CSF sampling study conducted at the Washington University School of Medicine in St. Louis. Older adults with amyloid deposition (Amyloid +), age-matched controls without amyloid deposition (Amyloid −), and younger normal controls (YNC) were enrolled for the study.
Main Outcome Measures
Hourly measurements of plasma Aβ were compared between groups by age and amyloidosis. Plasma Aβ and CSF Aβ levels were compared for correlation, linear increase, and circadian patterns.
Circadian patterns were observed in plasma Aβ, with diminished amplitudes with aging. Linear increase of Aβ was only observed for CSF Aβ in YNC and Amyloid − groups, but not in the Amyloid + group. No linear increase was observed for plasma Aβ. No significant correlations were found between plasma and CSF Aβ levels.
Plasma Aβ, like CSF, demonstrates a circadian pattern which is reduced in amplitude with increasing age but is unaffected by amyloid deposition. However, we found no evidence that plasma and CSF Aβ levels were related on an hourly or individual basis.
PMCID: PMC3808092  PMID: 23229043
18.  Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline 
Neurology  2012;79(16):1636-1644.
Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.
A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ−) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.
In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating–sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ− subjects (p < 0.10).
Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.
PMCID: PMC3468774  PMID: 22786606
19.  Amyloid Deposition, Hypometabolism, and Longitudinal Cognitive Decline 
Annals of neurology  2012;72(4):578-586.
Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross-sectional relationships between amyloid deposition, hypometabolism, and cognition, and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements.
We examined associations between mean cortical florbetapir uptake, mean 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) within a set of predefined regions, and Alzhiemer’s Disease Assessment Scale (ADAS-cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment [EMCI], 85 late MCI [LMCI], 53 Alzheimer disease [AD] patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG-PET were associated with retrospective decline in longitudinal ADAS-cog measurements.
Twenty-nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS-cog in both MCI groups. In longitudinal analyses, florbetapir-positive subjects in both normal and LMCI groups had greater ongoing ADAS-cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS-cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir.
Although both hypometabolism and β-amyloid (Aβ) deposition are detectable in normal subjects and all diagnostic groups, Aβ showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline.
PMCID: PMC3786871  PMID: 23109153
20.  Amyloid-β Imaging with Pittsburgh Compound B and Florbetapir: Comparing Radiotracers and Quantification Methods 
11C-Pittsburgh compound B (11C-PiB) and 18F-florbetapir amyloid-β (Aβ) PET radioligands have had a substantial impact on Alzheimer disease research. Although there is evidence that both radioligands bind to fibrillar Aβ in the brain, direct comparisons in the same individuals have not been reported. Here, we evaluated PiB and florbetapir in a retrospective convenience sample of cognitively normal older controls, patients with mild cognitive impairment, and patients with Alzheimer disease from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
From the ADNI database, 32 participants were identified who had undergone at least 1 PiB study and subsequently underwent a florbetapir study approximately 1.5 y after the last PiB study. Cortical PiB and florbetapir retention was quantified using several different methods to determine the effect of preprocessing factors (such as smoothing and reference region selection) and image processing pipelines.
There was a strong association between PiB and florbetapir cortical retention ratios (Spearman ρ = 0.86–0.95), and these were slightly lower than cortical retention ratios for consecutive PiB scans (Spearman ρ = 0.96–0.98) made approximately 1.1 y apart. Cortical retention ratios for Aβ-positive subjects tended to be higher for PiB than for florbetapir images, yielding slopes for linear regression of florbetapir against PiB of 0.59–0.64. Associations between consecutive PiB scans and between PiB and florbetapir scans remained strong, regardless of processing methods such as smoothing, spatial normalization to a PET template, and use of reference regions. The PiB–florbetapir association was used to interconvert cutoffs for Aβ positivity and negativity between the 2 radioligands, and these cutoffs were highly consistent in their assignment of Aβ status.
PiB and florbetapir retention ratios were strongly associated in the same individuals, and this relationship was consistent across several data analysis methods, despite scan–rescan intervals of more than a year. Cutoff thresholds for determining positive or negative Aβ status can be reliably transformed from PiB to florbetapir units or vice versa using a population scanned with both radioligands.
PMCID: PMC3747730  PMID: 23166389
amyloid-β; Alzheimer’s disease; PET imaging
21.  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.
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).
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.
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).
Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled.
This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.
PMCID: PMC3598572  PMID: 22397889
Vagus nerve stimulation; Depression; Positron emission tomography; Treatment-resistant depression; Fluorodeoxyglucose PET; Treatment response
22.  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
23.  Brain Blood-flow Change with Acute Vagus Nerve Stimulation in Treatment-Refractory Major Depressive Disorder 
Brain Stimulation  2011;5(2):163-171.
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.
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).
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.
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.
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.
PMCID: PMC3270206  PMID: 22037127
Vagus nerve stimulation; Depression; Positron emission tomography; Regional blood flow; Treatment-resistant depression
24.  [3H]4-(Dimethylamino)-N-(4-(4-(2-Methoxyphenyl)Piperazin-1-yl)-Butyl)Benzamide: A Selective Radioligand for Dopamine D3 receptors. II. Quantitative Analysis of Dopamine D3 and D2 Receptor Density Ratio in the Caudate-Putamen 
Synapse (New York, N.Y.)  2010;64(6):449-459.
4-(Dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-benzamide (WC-10), a N-phenyl piperazine analog, displays high affinity and moderate selectivity for dopamine D3 receptors versus dopamine D2 receptors (Chu et al. [2005] Bioorg Med Chem 13:77–87). In this study, WC-10 was radiolabeled with tritium (specific activity = 80 Ci/mmol), and quantitative autoradiography studies were conducted using rhesus monkey and Sprague-Dawley rat brain sections. Kd values for the binding of [3H]WC-10 to D3 receptors obtained from quantitative autoradiography with rhesus monkey and rat brain sections are in agreement with Kd values obtained from cloned human and rat receptors (Xu et al. [2009] Synapse 63:717-728). The D2 selective antagonist [3H]raclopride binds with 11-fold higher affinity to human HEK D2L (Kd = 1.6 nM) than HEK D3 (Kd = 18 nM) receptors; [3H]raclopride binds to rat Sf9 rD2L receptors with a Kd of 6.79 nM, a value that is 4-fold lower than binding to human HEK D2L receptors and 2.5-fold higher than binding to rat Sf9 rD3 receptors. In vitro quantitative autoradiography studies with [3H]WC-10 and [3H]raclopride were conducted on adult rat and rhesus monkey brain sections. A mathematical model for calculating the absolute densities of dopamine D2 and D3 receptors based on the in vitro receptor binding data of [3H]WC-10 and [3H]raclopride was developed.
PMCID: PMC3583018  PMID: 20175227
dopamine; DA D3/D2 receptors; quantitative autoradiography
25.  Exercise engagement as a moderator of APOE effects on amyloid deposition 
Archives of neurology  2012;69(5):636-643.
APOE ε4 status has been associated with greater cortical amyloid deposition whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.
APOE genotyping and a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with PET-PIB. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.
201 cognitively normal adults (135 females) aged 45–88 were recruited from the Knight Alzheimer Disease Research Center at Washington University. CSF samples were collected from 165 participants. Amyloid imaging was performed on 163 participants.
APOE ε4 carriers evidenced higher PIB binding (p<.001) and lower CSF Aβ42 levels (p<.001) than non-carriers. Our previous findings of higher PIB binding (p=.005) and lower CSF Aβ42 levels (p=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p=.008) such that a more sedentary lifestyle was significantly associated with higher PIB binding for ε4 carriers (p=.013) but not for ε4 non-carriers (p=.208). All findings remained significant after controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems, history of depression and interval between assessments.
Collectively, these results suggest that cognitively normal sedentary APOE ε4+ individuals may be at augmented risk for cerebral amyloid deposition.
PMCID: PMC3583203  PMID: 22232206

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