The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [18F]ASEM.

Altered function of the alpha7 nicotinic acetylcholine receptor (α7-nAChR) is implicated in several neuropsychiatric diseases. Nevertheless, studies of the human cerebral α7-nAChR even in healthy aging are limited in number and to postmortem tissue. METHODS: The distribution of the cerebral α7-nAChR was estimated in nine brain regions in 25 healthy volunteers (ages 21-86 years; median 57 years, interquartile range 52 years) using [18F]ASEM with positron emission tomography (PET) imaging. Regional total distribution volume (VT) measurements were calculated using the Logan method from each subject's 90 min dynamic PET data and their metabolite-corrected plasma input function. Spearman's rank or Pearson's correlation analysis was used depending on the normality of the data. Correlation between age and regional 1) volume relative to intracranial volume (volume ratio) and 2) [18F]ASEM VT was tested. Correlation between regional volume ratio and [18F]ASEM VT was also evaluated. Finally, the relationship between [18F]ASEM VT and neuropsychological measures was investigated in a subpopulation of 15 elderly healthy participants (those 50 years of age and older). Bonferroni correction for multiple comparisons was applied to statistical analyses. RESULTS: A negative correlation between tissue volume ratio and age was observed in six of the nine brain regions including striatum and five cortical (temporal, occipital, cingulate, frontal, or parietal) regions. A positive correlation between [18F]ASEM VT and age was observed in all nine brain regions of interest (ROIs). There was no correlation between [18F]ASEM VT and volume ratio in any ROI after controlling for age. Regional [18F]ASEM VT and neuropsychological performance on each of eight representative subtests were not correlated among the well-performing subpopulation of elderly healthy participants. CONCLUSIONS: Our results suggest an increase in cerebral α7-nAChR distribution over the course of healthy aging that should be tested in future longitudinal studies. The preservation of the α7-nAChR in the aging human brain supports the development of therapeutic agents that target this receptor for use in the elderly. Further study of the relationship between α7-nAChR availability and cognitive impairment over aging is needed.

Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (+/-)3,4-methylenedioxymethamphetamine ("ecstasy") users: relationship to cognitive performance.

BACKGROUND: (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. This study sought to determine whether MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations, develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance. MATERIALS AND METHODS: Sixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing. RESULTS: MDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship. CONCLUSIONS: Use of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density.

Quantitative positron emission tomography studies of the serotonin transporter in humans previously treated with the appetite suppressants fenfluramine or dexfenfluramine.

PURPOSE: The appetite suppressants fenfluramine and dexfenfluramine were widely prescribed before being withdrawn from the market in 1997. Both drugs are known to have the potential to damage brain serotonin (5-HT) axons and axon terminals in animals, including nonhuman primates. This study used quantitative positron emission tomography (PET) with [(11)C] McN5652, a serotonin transporter (SERT) ligand to determine whether humans previously exposed to fenfluramines showed reductions in SERT binding parameters. PROCEDURES: Subjects previously treated with fenfluramines for weight loss (N = 15) and age-matched controls (N = 17) underwent PET studies with [(11)C] McN5652. Global and regional distribution volumes (DVs) of [(11)C] McN5652 were compared in the two subject groups using parametric statistical analyses. RESULTS: Compared to controls, subjects previously exposed to fenfluramines had significant reductions in [(11)C]McN5652 binding in 14 of 15 regions of interest, more than four years after drug discontinuation. CONCLUSIONS: These results are the first to provide direct evidence for fenfluramine-induced 5-HT neurotoxicity in humans.

Imaging of Glial Cell Activation and White Matter Integrity in Brains of Active and Recently Retired National Football League Players.

IMPORTANCE: Microglia, the resident immune cells of the central nervous system, play an important role in the brain's response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury. OBJECTIVE: To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level-, and body mass index-matched control participants. This study was conducted at an academic research institution in Baltimore, Maryland, from January 29, 2015, to February 18, 2016. MAIN OUTCOMES AND MEASURES: Positron emission tomography-based regional measures of TSPO using [11C]DPA-713, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural magnetic resonance imaging, and neuropsychological performance. RESULTS: The mean (SD) ages of the 14 NFL participants and 16 control participants were 31.3 (6.1) years and 27.6 (4.9) years, respectively. Players reported a mean (SD) of 7.0 (6.4) years (range, 1-21 years) since the last self-reported concussion. Using [11C]DPA-713 positron emission tomographic data from 12 active or former NFL players and 11 matched control participants, the NFL players showed higher total distribution volume in 8 of the 12 brain regions examined (P < .004). We also observed limited change in white matter fractional anisotropy and mean diffusivity in 13 players compared with 15 control participants. In contrast, these young players did not differ from control participants in regional brain volumes or in neuropsychological performance. CONCLUSIONS AND RELEVANCE: The results suggest that localized brain injury and repair, indicated by higher TSPO signal and white matter changes, may be associated with NFL play. Further study is needed to confirm these findings and to determine whether TSPO signal and white matter changes in young NFL athletes are related to later onset of neuropsychiatric symptoms.

Psychiatric and cognitive effects of war in former yugoslavia: association of lack of redress for trauma and posttraumatic stress reactions.

CONTEXT: Although impunity for those responsible for trauma is widely thought to be associated with psychological problems in survivors of political violence, no study has yet investigated this issue. OBJECTIVE: To examine the mental health and cognitive effects of war trauma and how appraisal of redress for trauma and beliefs about justice, safety, other people, war cause, and religion relate to posttraumatic stress responses in war survivors. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey conducted between March 2000 and July 2002 with a population-based sample of 1358 war survivors who had experienced at least 1 war-related stressor (combat, torture, internal displacement, refugee experience, siege, and/or aerial bombardment) from 4 sites in former Yugoslavia, accessed through linkage sampling. Control groups at 2 study sites were matched with survivors on sex, age, and education. MAIN OUTCOME MEASURES: Semi-structured Interview for Survivors of War, Redress for Trauma Survivors Questionnaire, Emotions and Beliefs After War questionnaire, Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). RESULTS: The mean (SD) age was 39 (12) years, 806 (59%) were men, and 339 (25%) had high school or higher level of education. Participants reported experiencing a mean of 12.6 war-related events, with 292 (22%) and 451 (33%) having current and lifetime posttraumatic stress disorder (PTSD), respectively, and 129 (10%) with current major depression. A total of 1074 (79%) of the survivors reported a sense of injustice in relation to perceived lack of redress for trauma. Perceived impunity for those held responsible for trauma was only one of the factors associated with sense of injustice. Relative to controls, survivors had stronger emotional responses to impunity, greater fear and loss of control over life, less belief in benevolence of people, greater loss of meaning in war cause, stronger faith in God, and higher rates of PTSD and depression. Fear and loss of control over life were associated with PTSD and depression (odds ratio [OR], 2.91; 95% CI, 2.27-3.74 and OR, 2.30; 95% CI, 1.75-3.03, respectively), and emotional responses to impunity showed a relatively weaker association with PTSD (OR, 1.53; 95% CI, 1.16-2.02) and depression (OR, 1.39; 95% CI, 1.02-1.91). Appraisal of redress for trauma was not associated with PTSD or depression. CONCLUSIONS: PTSD and depression in war survivors appear to be independent of sense of injustice arising from perceived lack of redress for trauma. Fear of threat to safety and loss of control over life appeared to be the most important mediating factors in PTSD and depression. These findings may have important implications for reconciliation efforts in postwar countries and effective interventions for traumatized war survivors.

Image-derived and arterial blood sampled input functions for quantitative PET imaging of the angiotensin II subtype 1 receptor in the kidney.

PURPOSE: The radioligand 11C-KR31173 has been introduced for positron emission tomography (PET) imaging of the angiotensin II subtype 1 receptor in the kidney in vivo. To study the biokinetics of 11C-KR31173 with a compartmental model, the input function is needed. Collection and analysis of arterial blood samples are the established approach to obtain the input function but they are not feasible in patients with renal diseases. The goal of this study was to develop a quantitative technique that can provide an accurate image-derived input function (ID-IF) to replace the conventional invasive arterial sampling and test the method in pigs with the goal of translation into human studies. METHODS: The experimental animals were injected with [11C]KR31173 and scanned up to 90 min with dynamic PET. Arterial blood samples were collected for the artery derived input function (AD-IF) and used as a gold standard for ID-IF. Before PET, magnetic resonance angiography of the kidneys was obtained to provide the anatomical information required for derivation of the recovery coefficients in the abdominal aorta, a requirement for partial volume correction of the ID-IF. Different image reconstruction methods, filtered back projection (FBP) and ordered subset expectation maximization (OS-EM), were investigated for the best trade-off between bias and variance of the ID-IF. The effects of kidney uptakes on the quantitative accuracy of ID-IF were also studied. Biological variables such as red blood cell binding and radioligand metabolism were also taken into consideration. A single blood sample was used for calibration in the later phase of the input function. RESULTS: In the first 2 min after injection, the OS-EM based ID-IF was found to be biased, and the bias was found to be induced by the kidney uptake. No such bias was found with the FBP based image reconstruction method. However, the OS-EM based image reconstruction was found to reduce variance in the subsequent phase of the ID-IF. The combined use of FBP and OS-EM resulted in reduced bias and noise. After performing all the necessary corrections, the areas under the curves (AUCs) of the AD-IF were close to that of the AD-IF (average AUC ratio=1±0.08) during the early phase. When applied in a two-tissue-compartmental kinetic model, the average difference between the estimated model parameters from ID-IF and AD-IF was 10% which was within the error of the estimation method. CONCLUSIONS: The bias of radioligand concentration in the aorta from the OS-EM image reconstruction is significantly affected by radioligand uptake in the adjacent kidney and cannot be neglected for quantitative evaluation. With careful calibrations and corrections, the ID-IF derived from quantitative dynamic PET images can be used as the input function of the compartmental model to quantify the renal kinetics of 11C-KR31173 in experimental animals and the authors intend to evaluate this method in future human studies.

Initial Evaluation of [(18)F]DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a recognized target for imaging prostate cancer. Here we present initial safety, biodistribution, and radiation dosimetry results with [(18)F]DCFPyL, a second-generation fluorine-18-labeled small-molecule PSMA inhibitor, in patients with prostate cancer. PROCEDURES: Biodistribution was evaluated using sequential positron-emission tomography (PET) scans in nine patients with prostate cancer. Time-activity curves from the most avid tumor foci were determined. The radiation dose to selected organs was estimated using OLINDA/EXM. RESULTS: No major radiotracer-specific adverse events were observed. Physiologic accumulation was observed in known sites of PSMA expression. Accumulation in putative sites of prostate cancer was observed (SUVmax up to >100, and tumor-to-blood ratios up to >50). The effective radiation dose from [(18)F]DCFPyL was 0.0139 mGy/MBq or 5 mGy (0.5 rem) from an injected dose of 370 MBq (10 mCi). CONCLUSIONS: [(18)F]DCFPyL is safe with biodistribution as expected, and its accumulation is high in presumed primary and metastatic foci. The radiation dose from [(18)F]DCFPyL is similar to that from other PET radiotracers.

Positron-emission tomography imaging of the angiotensin II subtype 1 receptor in swine renal artery stenosis.

The angiotensin II subtype 1 receptor (AT(1)R) has been linked to the development and progression of renovascular hypertension. In this study we applied a pig model of renovascular hypertension to investigate the AT(1)R in vivo with positron-emission tomography (PET) and in vitro with quantitative autoradiography. AT(1)R PET measurements were performed with the radioligand [(11)C]KR31173 in 11 control pigs and in 13 pigs with hemodynamically significant renal artery stenosis; 4 were treated with lisinopril for 2 weeks before PET imaging. The radioligand impulse response function was calculated by deconvolution analysis of the renal time-activity curves. Radioligand binding was quantified by the 80-minute retention of the impulse response function. Median values and interquartile ranges were used to illustrate group statistics. Radioligand retention was significantly increased (P=0.044) in hypoperfused kidneys of untreated (0.225; range: 0.150 to 0.373) and lisinopril-treated (0.237; range:0.224 to 0.272) animals compared with controls (0.142; range:0.096 to 0.156). Increased binding of [(11)C]KR31173 documented by PET in vivo was confirmed by in vitro autoradiography. Both in vivo and in vitro binding measurements showed that the effect of renal artery stenosis on the AT(1)R was not abolished by lisinopril treatment. These studies provide insight into kidney biology as the first in vivo/in vitro experimental evidence about AT(1)R regulation in response to reduced perfusion of the kidney. The findings support the concept of introducing AT(1)R PET as a diagnostic biomarker of renovascular disease.