Carolyn C. Meltzer

Kinetic Modeling of Amyloid Binding in Humans using PET Imaging and Pittsburgh Compound-B

A valid quantitative imaging method for the measurement of amyloid deposition in humans could improve Alzheimers disease (AD) diagnosis and antiamyloid therapy assessment. Our group developed Pittsburgh Compound-B (PIB), an amyloid-binding radiotracer, for positron emission tomography (PET). The current study was aimed to further validate PIB PET through quantitative imaging (arterial input) and inclusion of subjects with mild cognitive impairment (MCI). Pittsburgh Compound-B studies were performed in five AD, five MCI, and five control subjects and five subjects were retested within 20 days. Magnetic resonance images were acquired for partial volume correction and region-of-interest definition (e.g., posterior cingulate: PCG; cerebellum: CER). Data were analyzed using compartmental and graphical approaches. Regional distribution volume (DV) values were normalized to the reference region (CER) to yield DV ratios (DVRs). Good agreement was observed between compartmental and Logan DVR values (e.g., PCG: r = 0.89, slope = 0.91); the Logan results were less variable. Nonspecific PIB retention was similar across subjects (n = 15, Logan CER DV: 3.63 ± 0.48). Greater retention was observed in AD cortical areas, relative to controls (P < 0.05). The PIB retention in MCI subjects appeared either ‘AD-like’ or ‘control-like’. The mean test/retest variation was ~6% in primary areas-of-interest. The Logan analysis was the method-of-choice for the PIB PET data as it proved stable, valid, and promising for future larger studies and voxel-based statistical analyses. This study also showed that it is feasible to perform quantitative PIB PET imaging studies that are needed to validate simpler methods for routine use across the AD disease spectrum.

Serotonin in Aging, Late-Life Depression, and Alzheimer's Disease: The Emerging Role of Functional Imaging

Serotonin (5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life may contribute to behavioral changes commonly observed in the elderly population. Extensive evidence implicates a deficit in serotonergic neurotransmission in the development of major depression. It has been further suggested that the age-related changes in 5-HT neurons may predispose the elderly to develop depression. There is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimers disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brian imaging with positron emission tomography (PET) in the in vivo study of the brain in aging, depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioral features of aging and to define and monitor therapeutic regimens for neuropsychiatric conditions of late life. Coupling of clinical trials in well-characterized subject populations with PET imaging using ligands specific for 5-HT receptor subtypes and transporter proteins promises to increase our understanding of the role of the 5-HT system in affective and cognitive aspects of treatment response. Longitudinal studies in aging, late-life depression, and AD are also needed to evaluate the complex interplay between neurodegenerative processes and serotonergic neurotransmission.

Correction of PET data for partial volume effects in human cerebral cortex by MR imaging.

Due to the limited spatial resolution of positron emission tomography (PET), the accuracy of quantitative measurements of regional metabolism or neuroreceptor concentration is influenced by partial volume averaging of brain with CSF, bone, and scalp. This effect is increased in the presence of cortical atrophy, as in patients with Alzheimer disease (AD). Correction for this underestimation in PET measurements is necessary for the comparison of AD patients and normal controls. We have developed a method for three-dimensional correction of human PET data using magnetic resonance (MR) imaging. A composite brain tissue image is created by summing the binary representation of nine MR images, weighted to the PET z-axis line-spread function. This composite tissue image is convolved to the resolution of the PET image. The original PET image is divided by the convolved tissue image on a pixel-by-pixel basis, resulting in an atrophy-corrected PET image in which count density represents activity per volume of brain tissue rather than spatial volume. This has been performed in [11C]carfentanil mu-opiate receptor PET studies of the temporal cortex in two AD patients and one normal volunteer. After correction, average regional increases in count density were 11% (range = 4–21%) in the normal and 46% (range = 28–99%) and 48% (range = 14–109%) in the patient studies. The accuracy of this method of partial volume correction was estimated using a spherical phantom.

Increased Dopamine D2/D3 Receptor Binding After Recovery from Anorexia Nervosa Measured by Positron Emission Tomography and [11C]Raclopride

BACKGROUND Several lines of evidence support the possibility that disturbances of dopamine (DA) function could contribute to alterations of weight, feeding, motor activity, and reward in anorexia nervosa (AN). METHODS To assess possibly trait-related disturbances but avoid confounding effects of malnutrition, 10 women who were recovered from AN (REC AN) were compared with 12 healthy control women (CW). Positron emission tomography with [(11)C]raclopride was used to assess DA D2/D3 receptor binding. RESULTS The women who were recovered from AN had significantly higher [(11)C]raclopride binding potential in the antero-ventral striatum than CW. For REC AN, [(11)C]raclopride binding potential was positively related to harm avoidance in the dorsal caudate and dorsal putamen. CONCLUSIONS These data lend support for the possibility that decreased intrasynaptic DA concentration or increased D2/D3 receptor density or affinity is associated with AN and might contribute to the characteristic harm avoidance or increased physical activity found in AN. Most intriguing is the possibility that individuals with AN might have a DA related disturbance of reward mechanisms contributing to altered hedonics of feeding behavior and their ascetic, anhedonic temperament.

A fenfluramine-activated FDG-PET study of borderline personality disorder

BACKGROUND Impulsive aggression in patients with personality disorders is associated with diminished levels of cerebrospinal fluid (CSF) 5-HIAA, blunted neuroendocrine responses to serotonergic agonists, and decreased glucose utilization in the prefrontal cortex. We tested the hypothesis that impulsive aggression in borderline personality disorder (BPD) may be associated with diminished serotonergic regulation in the prefrontal cortex, using positron-emission tomography (PET) neuroimaging during pharmacologic challenge with d,l fenfluramine (FEN). METHODS A 2-day, single-blind, placebo-controlled FEN challenge study was conducted in five patients with BPD (and no Axis I MDD) and eight healthy control participants. On Day 1, 4 mCi [(18)F]-fluorodeoxyglucose (FDG) was injected 3 hours after ingestion of placebo; on Day 2, FDG was injected 3 hours after ingestion of.8 mg/kg to 60 mg of d,l fenfluramine. After 30 min, a 45-min emission scan was acquired on the Siemans/CTI 951r/31 scanner. PET data were aligned to MR images and analyzed by Statistical Parametric Mapping (SPM96). RESULTS In response to placebo, uptake of FDG was greater in control participants than patients in large areas of the prefrontal cortex including medial and orbital regions bilaterally (BA 10-11), left superior temporal gyrus, and right insular cortex. There were no areas in which patients had greater relative regional uptake than control participants. In response to FEN, relative regional uptake of FDG (relative to placebo) was greater in control participants compared to patients in medial and orbital regions of right prefrontal cortex (BA 10), left middle and superior temporal gyri (BA 22-23), left parietal lobe (BA 40), and left caudate body. CONCLUSIONS Patients with BPD have diminished response to serotonergic stimulation in areas of prefrontal cortex associated with regulation of impulsive behavior.

Combined PET/CT Imaging in Oncology: Impact on Patient Management

Purpose: In this work, we describe five oncology patients whose clinical management were uniquely benefited by a novel scanner that acquires positron emission tomography (PET) and x-ray computed tomography (CT) in the same imaging session.Procedures: Co-registered 2-[F(18)]-fluoro-2-deoxy-D-glucose (FDG)-PET and CT images were acquired using a combined PET/CT scanner. Pathology and clinical follow-up data were used to confirm PET/CT scan results.Results: The combined PET/CT scanner demonstrated the ability to distinguish malignant lesions from normal physiologic FDG uptake in the striated muscles of the head and neck as well as excretory and bowel activity in the abdomen and pelvis. Additionally, the technology positively affected patient management through localization for surgical and radiation therapy planning as well as assessment of tumor response.Conclusion: Our experience indicates that simultaneous acquisition of co-registered PET and CT images enabled physicians to more precisely discriminate between physiologic and malignant FDG uptake and more accurately localize lesions, improving the value of diagnostic PET in oncologic applications.

Impulsivity and prefrontal hypometabolism in borderline personality disorder.

Prefrontal hypoperfusion and decreased glucose uptake in the prefrontal cortex (PFC) are found in violent criminal offenders, murderers and aggressive psychiatric patients. These abnormalities may be independent of diagnosis and associated with impulsive-aggression as a personality trait. Impulsive-aggression is a clinical characteristic of borderline personality disorder (BPD) where it is associated with assaultive and suicidal behaviors. We conducted FDG-PET studies in 13 non-depressed, impulsive female subjects with BPD and 9 healthy controls to look for abnormalities in glucose metabolism in areas of the PFC associated with regulation of impulsive behavior. Statistical Parametric Mapping-99 (SPM99) was used to analyze the PET data with Hamilton depression scores as covariate. Significant reductions in FDG uptake in BPD subjects relative to healthy controls were found bilaterally in medial orbital frontal cortex, including Brodmanns areas 9, 10 and 11. There were no significant areas of increased uptake in BPD subjects compared to control subjects. Covarying for measures of impulsivity or impulsive-aggression rendered insignificant the differences between groups. Decreased glucose uptake in medial orbital frontal cortex may be associated with diminished regulation of impulsive behavior in BPD.

Role of Positron Emission Tomography in Staging Esophageal Cancer

BACKGROUND Conventional noninvasive staging of esophageal cancer is inaccurate. This study investigated the role of positron emission tomography (PET) in staging esophageal cancer. METHODS Patients with potentially resectable esophageal cancer were included. A whole-body PET scan was acquired after injection of 18F-fluorodeoxyglucose and was evaluated for areas of increased focal uptake. Accuracy was determined by comparing PET with surgical staging. RESULTS Potentially resectable esophageal cancer was identified in 35 patients. Positron emission tomography detected nine sites of distant metastases missed by conventional scanning, but one false-negative PET scan occurred in a patient with a 2-mm liver lesion. There were 11 false-negative PET scans for small, intracapsular local-regional nodal metastases (mean diameter 5.2 mm; range 2 to 10 mm). For distant metastases, the sensitivity was 88%, the specificity was 93%, and the accuracy was 91%. For local-regional nodal metastases, the sensitivity was 45%, the specificity was 100%, and the accuracy was 48%. CONCLUSIONS Positron emission tomography improved our ability to detect distant metastases missed by conventional noninvasive staging of esophageal cancer. Small local-regional nodal metastases are not identified by current PET technology. Early use of PET in the staging of patients with esophageal cancer could facilitate treatment planning and identifying unsuspected distant metastases in up to 20% of patients with a negative metastatic survey by conventional staging.

Serotonin 1A receptor binding and treatment response in late-life depression.

Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT1A) receptor as a regulator of treatment response, particularly the 5-HT1A autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT1A receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4±5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0±6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP=2.31±0.90) relative to control (BP=3.69±1.56) subjects (p=0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r=0.60, p=0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r=0.52, p=0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT1A autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression.

Reduced 5-HT2A receptor binding after recovery from anorexia nervosa

BACKGROUND Several lines of evidence suggest that a disturbance of serotonin neuronal pathways may contribute to the pathogenesis of anorexia nervosa (AN). This study applied positron emission tomography (PET) to investigate the brain serotonin 2A (5HT2A) receptor, which could contribute to disturbances of appetite and behavior in AN. METHODS To avoid the confounding effects of malnutrition, we studied 16 women recovered from AN (REC AN, >1 year normal weight, regular menstrual cycles, no bingeing or purging) compared with 23 healthy control women (CW) using [18F]altanserin, a specific 5-HT2A receptor antagonist on PET imaging. RESULTS REC AN women had significantly reduced [18F]altanserin binding relative to CW in mesial temporal (amygdala and hippocampus), as well as cingulate cortical regions. In a subset of subjects (11 CW and 16 REC AN), statistical parametric mapping (SPM) confirmed reduced mesial temporal cortex 5HT2A receptor binding and, in addition, showed reduced occipital and parietal cortex binding. CONCLUSIONS This study extends research suggesting that altered 5-HT neuronal system activity persists after recovery from AN and may be related to disturbances of mesial temporal lobe function. Altered 5-HT neurotransmission after recovery also supports the possibility that this may be a trait-related disturbance that contributes to the pathophysiology of AN.