Dataset Information

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study.

ABSTRACT: PURPOSE:The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. METHODS:[11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N?=?78 with HAB and N?=?62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N?=?53), Turku PET centre (N?=?62) and Yale University PET Center (N?=?25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. RESULTS:There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. CONCLUSION:These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

SUBMITTER: Tuisku J

PROVIDER: S-EPMC6717599 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [<sup>11</sup>C]PBR28 HRRT PET study.

Tuisku Jouni J Plavén-Sigray Pontus P Gaiser Edward C EC Airas Laura L Al-Abdulrasul Haidar H Brück Anna A Carson Richard E RE Chen Ming-Kai MK Cosgrove Kelly P KP Ekblad Laura L Esterlis Irina I Farde Lars L Forsberg Anton A Halldin Christer C Helin Semi S Kosek Eva E Lekander Mats M Lindgren Noora N Marjamäki Päivi P Rissanen Eero E Sucksdorff Marcus M Varrone Andrea A Collste Karin K Gallezot Jean-Dominique JD Hillmer Ansel A Huang Yiyun Y Höglund Caroline O CO Johansson Jarkko J Jucaite Aurelija A Lampa Jon J Nabulsi Nabeel N Pittman Brian B Sandiego Christine M CM Stenkrona Per P Rinne Juha J Matuskey David D Cervenka Simon S

European journal of nuclear medicine and molecular imaging 20190730 11

<h4>Purpose</h4>The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [<sup>11</sup>C]PBR28.<h4>Methods</h4>[<sup>11</sup>C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at ...[more]

PMID: 31363804

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Project description:The translocator protein (TSPO) is a commonly used imaging target to investigate neuroinflammation. Although TSPO imaging demonstrates great promise, its signal exhibits substantial interindividual variability, which needs to be accounted for to uncover group effects that are truly reflective of neuroimmune activation. Recent evidence suggests that relative metrics computed using pseudoreference approaches can minimize within-group variability and increase sensitivity to detect physiologically meaningful group differences. Here, we evaluated various ratio approaches for TSPO imaging and compared them with standard kinetic modeling techniques, analyzing 2 different disease cohorts. Patients with chronic low back pain (cLBP) or amyotrophic lateral sclerosis (ALS) and matching healthy controls received 11C-PBR28 PET scans. The occipital cortex, cerebellum and whole brain were first evaluated as candidate pseudoreference regions by testing for the absence of group differences in SUV and distribution volume (VT) estimated with an arterial input function. The SUV from target regions (cLBP study, thalamus; ALS study, precentral gyrus) was normalized with the SUV from candidate pseudoreference regions (i.e., occipital cortex, cerebellum, and whole brain) to obtain SUVRoccip, SUVRcereb, and SUVRWB The sensitivity to detect group differences in target regions was compared using various SUVR approaches, as well as distribution volume ratio (DVR) estimated with (blDVR) or without arterial input function (refDVR), and VT Additional voxelwise SUVR group analyses were performed. We observed no significant group differences in pseudoreference VT or SUV, excepting whole-brain VT, which was higher in cLBP patients than controls. Target VT elevations in patients (P = 0.028 and 0.051 in cLBP and ALS, respectively) were similarly detected by SUVRoccip and SUVRWB, and by refDVR and blDVR (less reliably by SUVRcereb). In voxelwise analyses, SUVRoccip, but not SUVRcereb, identified regional group differences initially observed with SUVRWB, and in additional areas suspected to be affected in the pathology examined. All ratio metrics were highly cross-correlated, but generally were not associated with VT. Although important caveats need to be considered when using relative metrics, ratio analyses appear to be similarly sensitive to detect pathology-related group differences in 11C-PBR28 signal as classic kinetic modeling techniques. The occipital cortex may be a suitable pseudoreference region, at least for the populations evaluated, pending further validation in larger cohorts.

Project description:Alzheimer's disease is associated with chronic response of innate immune system, referred as neuroinflammation. PET radioligands binding to the 18?kDa translocator protein are potential biomarkers of neuroinflammation. Translocator protein PET studies in mild cognitive impairment and Alzheimer's disease have indicated controversial results, possibly reflecting interindividual variation and heterogeneity of study populations. We controlled for genetic and environmental effects by studying twin pairs discordant for episodic memory performance. Episodic memory impairment is a well-known cognitive hallmark of early Alzheimer's disease process. Eleven same-sex twin pairs (four monozygotic pairs, six female pairs, age 72-77?years) underwent [11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([11C]PBR28) PET imaging, structural magnetic resonance imaging and neuropsychological testing in 2014-17. Main PET outcome was the volume-weighted average standardized uptake value of cortical regions vulnerable to Alzheimer's disease pathology. Ten pairs were discordant for episodic memory performance. In the eight pairs with identical translocator protein genotype, twins with poorer episodic memory had ?20% higher cortical [11C]PBR28 binding compared with their better-performing co-twins (mean intra-pair difference 0.21 standardized uptake value, 95% confidence interval 0.05-0.37, P?=?0.017). The result remained the same when including all discordant pairs and controlling for translocator protein genotype. Increased translocator protein PET signal suggests that increased microglial activation is associated with poorer episodic memory performance. Twins with worse episodic memory performance compared with their co-twins had on average 20% higher uptake of the neuroinflammatory marker translocator protein PET tracer 11[11C]PBR28. The findings support a negative association between neuroinflammation and episodic memory and the use of translocator protein positron emission tomography as a useful indicator of Alzheimer's disease process.

Dataset Information

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study.

Publications

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [<sup>11</sup>C]PBR28 HRRT PET study.

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