To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Abeta) deposition in vivo in individuals without dementia.
(11)CPiB images were obtained ...to measure fibrillar Abeta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure (11)CPiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations.
(11)CPiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions.
Higher Abeta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Abeta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.
Several lines of evidence suggest aberrant immune response in schizophrenia, including elevated levels of cytokines. These cytokines are thought to be produced by activated microglia, the innate ...immune cells of the central nervous system. However, increase in translocator protein 18 kDa (TSPO), a marker of activated glia, has not been found in patients with chronic schizophrenia using second-generation radiotracers and positron emission tomography (PET)-based neuroimaging. In this study we focused on patients with recent onset of schizophrenia (within 5 years of diagnosis). Quantified levels of TSPO in the cortical and subcortical brain regions using the PET-based radiotracer (11)CDPA-713 were compared between the patients and healthy controls. Markers of inflammation, including interleukin 6 (IL-6), were assessed in the plasma and cerebrospinal fluid (CSF) in these participants. We observed no significant change in the binding of (11)CDPA-713 to TSPO in 12 patients with recent onset of schizophrenia compared with 14 controls. Nevertheless, the patients with recent onset of schizophrenia showed a significant increase in IL-6 in both plasma (P<0.001) and CSF (P=0.02). The CSF levels of IL-6 were significantly correlated with the levels of IL-6 in plasma within the total study population (P<0.001) and in patients with recent onset of schizophrenia alone (P=0.03). Our results suggest that increased levels of IL-6 may occur in the absence of changed TSPO PET signal in the brains of medicated patients with recent onset of schizophrenia. Future development of PET-based radiotracers targeting alternative markers of glial activation and immune response may be needed to capture the inflammatory signature present in the brains of patients with early-stage disease.
OBJECTIVE: Both age and gender are being increasingly recognized as important factors influencing CNS structure and function. However, there are relatively few data on actual neurochemical ...differences between the sexes in human subjects or on their interaction with age. One of the central neurotransmitter systems for which sex differences have been suggested by animal models and clinical human data is the opioid. In this study the authors examined age- and gender-associated variations in mu-opioid receptor binding with positron emission tomography (PET). METHOD: Healthy human subjects were studied with PET and the radiotracer 11Ccarfentanil, a selective mu-opioid agonist. Two separate subject groups were examined: one group of 24 men and 12 women was studied in a retrospective analysis of data, and a second group of 12 men and 18 women was recruited prospectively and studied with a higher-resolution scanner. RESULTS: Mu-opioid receptor binding potential (Bmax Kd) was found to increase with age in neocortical areas and the putamen. Sex differences, with higher mu-opioid binding in women, were observed in a number of cortical and subcortical areas. Gender-by-age interactions were observed in the thalamus and the amygdala; in vivo mu-opioid binding declined in postmenopausal women to levels below those of men. CONCLUSIONS: These data imply that both age and gender are important variables to consider in the interpretation of investigations of human function in which the opioid system plays a role. Also, women's reproductive status (reproductive age versus postmenopausal) may influence the function of CNS opioid systems.
Cocaine treatment upregulates brain mu-opioid receptors (mOR) in animals. Human data regarding this phenomenon are limited. We previously used positron emission tomography (PET) with
11C-carfentanil ...to show increased mOR binding in brain regions of 10 cocaine-dependent men after 1 and 28 days of abstinence.
Regional brain mOR binding potential (BP) was measured with
11Ccarfentanil PET scanning in 17 cocaine users over 12 weeks of abstinence on a research ward and in 16 healthy control subjects.
Mu-opioid receptor BP was increased in the frontal, anterior cingulate, and lateral temporal cortex after 1 day of abstinence. Mu-opioid receptor BP remained elevated in the first two regions after 1 week and in the anterior cingulate and anterior frontal cortex after 12 weeks. Increased binding in some regions at 1 day and 1 week was positively correlated with self-reported cocaine craving. Mu-opioid receptor BP was significantly correlated with percentage of days with cocaine use and amount of cocaine used per day of use during the 2 weeks before admission and with urine benzoylecgonine concentration at the first PET scan.
These results suggest that chronic cocaine use influences endogenous opioid systems in the human brain and might explain mechanisms of cocaine craving and reinforcement.
(±)3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a popular recreational drug that selectively damages brain serotonin (5-HT) neurons in animals at doses that closely approach those used by ...humans. We investigated the status of brain 5-HT neurons in MDMA users.
We enrolled 14 previous users of MDMA who were currently abstaining from use and 15 controls who had never used MDMA. We used positron emission tomography (PET) with the radioligand carbon-11-labelled McN-5652, which selectively labels the 5-HT transporter. We analysed whether there were differences in 5-HT transporter binding between abstinent MDMA users and participants in the control group. Blood and urine samples were taken and tested to check for abstinence.
MDMA users showed decreased global and regional brain 5-HT transporter binding compared with controls. Decreases in 5-HT transporter binding positively correlated with the extent of previous MDMA use.
Quantitative PET studies with a ligand selective for 5-HT transporters can be used to assess the status of 5-HT neurons in the living human brain. We show direct evidence of a decrease in a structural component of brain 5-HT neurons in human MDMA users.
Methamphetamine and methcathinone are psychostimulant drugs with high potential for abuse. In animals, methamphetamine and related drugs are known to damage brain dopamine (DA) neurons, and this ...damage has recently been shown to be detectable in living nonhuman primates by means of positron emission tomography (PET) with 11CWIN-35,428, a DA transporter (DAT) ligand. The present studies determined whether living humans with a history of methamphetamine or methcathinone abuse showed evidence of lasting decrements in brain DAT density. PET studies were performed in 10 control subjects, six abstinent methamphetamine users, four abstinent methcathinone users, and three patients with Parkinson's disease (PD). On average, subjects had abstained from amphetamine use for approximately 3 years. Before PET studies, all subjects underwent urine and blood toxicology screens to rule out recent drug use. Compared with controls, abstinent methamphetamine and methcathinone users had significant decreases in DAT density in the caudate nucleus (-23 and -24%, respectively) and putamen (-25 and -16%, respectively). Larger decreases in DAT density were evident in patients with PD (47 and 68% in caudate and putamen, respectively). Neither methamphetamine nor methcathinone users showed clinical signs of parkinsonism. Persistent reductions of DAT density in methamphetamine and methcathinone users are suggestive of loss of DAT or loss of DA terminals and raise the possibility that as these individuals age, they may be at increased risk for the development of parkinsonism or neuropsychiatric conditions in which brain DA neurons have been implicated.
Objective To examine the association between regional brain uptake of a novel amyloid positron emission tomography (PET) tracer florbetapir F 18 (18 F-AV-45) and cognitive performance in a pilot ...study. Design Cross-sectional comparison of 18 F-AV-45 in AD patients versus controls. Setting Three specialty memory clinics. Participants Eleven participants with probable Alzheimer disease (AD) by NINDS/ADRDA criteria and 15 healthy comparison (HC) participants. Measurements Participants underwent PET imaging following a 370 MBq (10 mCi) intravenous administration of 18 F-AV-45. Regional/cerebellar standardized uptake value ratios (SUVRs) were calculated. Cognition was assessed using Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Wechsler Logical Memory IA (immediate recall) test (LMIA), and verbal category fluency. Results Greater 18 F-AV-45 SUVR was associated with poorer performance on all cognitive tests. In the HC group, occipital, parietal, precuneus, temporal, and cortical average SUVR was associated with greater ADAS-Cog, and greater anterior cingulate SUVR was associated with lower LMIA. Two HC participants had 18 F-AV-45 cortical/cerebellar SUVR greater than 1.5, one of whom had deficits in episodic recall and on follow-up met criteria for amnestic mild cognitive impairment. Conclusion 18 F-AV-45 SUVR in several brain regions was associated with worse global cognitive performance particularly in HC, suggesting its potential as a marker of preclinical AD.
The role of the supraspinal endogenous opioid system in pain processing has been investigated in this study using positron emission tomography imaging of
11C-carfentanil, a synthetic, highly ...specific μ opioid receptor (μ-OR) agonist. Eight healthy volunteers were studied during a baseline imaging session and during a session in which subjects experienced pain induced by applying capsaicin topically to the dorsal aspect of the left hand. A pain-related decrease in brain μ-OR binding was observed in the contralateral thalamus consistent with competitive binding between
11C-carfentanil and acutely released endogenous opioid peptides. This decrease varied directly with ratings of pain intensity. These results suggest that the supraspinal μ-opioid system is activated by acute pain and thus may play a substantial role in pain processing and modulation in pain syndromes.
Purpose: Prostate-specific membrane antigen (PSMA) is a cell surface protein that is overexpressed in prostate cancer, including hormone-refractory
and metastatic disease. Our goal in this study was ...to develop a series of PSMA-based imaging agents for clinical use.
Experimental Design: We have synthesized and evaluated the in vivo biodistribution of two radiolabeled urea derivatives that have high affinity for PSMA in severe combined immunodeficient
mice harboring MCF-7 (breast, PSMA-negative), PC-3 (prostate, PSMA-negative), and LNCaP (prostate, PSMA-positive) xenografts.
Radiopharmaceutical binding selectivity and tumor uptake were also evaluated in vivo using dedicated small animal positron emission tomography, single photon emission computed tomography, and gamma scintigraphic
imaging devices. N - N -( S )-1,3-dicarboxypropylcarbamoyl- S - 11 Cmethyl- l -cysteine ( 11 CDCMC K i , 3.1 nmol/L) and N - N -( S )-1,3-dicarboxypropylcarbamoyl- S -3- 125 Iiodo- l -tyrosine ( 125 CDCIT K i , 1.5 nmol/L) were synthesized using 11 CCH 3 I and with 125 INaI/Iodogen, respectively.
Results: At 30 minutes postinjection, 11 CDCMC and 125 IDCIT showed tumor/muscle ratios of 10.8 and 4.7, respectively, with clear delineation of LNCaP-derived tumors on imaging.
MCF-7- and PC-3-derived tumors showed significantly less uptake of 11 CDCMC or 125 IDCIT.
Conclusion: These results show the feasibility of imaging PSMA-positive prostate cancer using low molecular weight agents.
A column-switch high performance liquid chromatography method for the analysis of 4 mL of plasma is described with six examples of chromatography of
11C-labeled positron-emission tomography imaging ...agents. Complete extraction of all but the most polar metabolites by the reverse phase capture column is achieved by disruption of plasma protein binding by 8 M urea.
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