Where in-vivo imaging meets cytoarchitectonics: The relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET
Research Highlights
► GABA-receptors were assessed with HRRT-PET as a surrogate for neuronal density (ND). ► ND was correlated with MRI-based cortical thickness measurement (SCT). ► In one subset ND was relatively constant and mainly independent of SCT. ► However, in another subset ND negatively correlated with SCT. ► Morphometry studies should be interpreted cautiously with regard on neuronal density.
Introduction
The thickness of the human cortex as a quantifiable parameter of cortical morphology has been of scientific and clinical interest for more than 100 years. The first comprehensive map of cortical thickness was published in the seminal work of Economo about the cytoarchitectonics of the adult human cortex in 1925 (Economo and Koskinas, 1925). Since the introduction of CT or MRI based tomographic imaging, changes (mainly decreases) of cortical gray matter have clinically been interpreted as atrophy and typical patterns of atrophy have been described in different kinds of degenerative diseases. Scientific interest in cortical volume measurements increased with the advent of standardized statistical methods like voxel-based morphometry (VBM) or surface cortical thickness (SCT) mapping for the analysis of gray matter changes in MR images. Using these methods, not only decreases but also increases in gray matter density have been described. These changes have been interpreted as changes in neuronal composition due to neuronal loss related to atrophy (Keller et al., 2002, Mueller et al., 2006, Wessels et al., 2006), or indicators of task-related neuronal plasticity (Maguire et al., 2000). The nature of the gray matter changes however is still poorly understood.
Many scientists using VBM or SCT methods implicitly assume that these measurements reflect the density of neuronal structures in the cortex, but systematic data for the entire brain are missing. This may be due to the fact that such a relationship is difficult to establish based on post-mortem histology because the in-vivo MRI must be done close in time to the post-mortem histology in order to avoid age or disease related changes. So far only one study has investigated the relationship between VBM and neuronal density in the mesial temporal cortex and no significant correlations between neuropathological measures and grey matter probability values were found (Eriksson et al., 2009). For neocortical areas however, no comparable data are available.
Positron-emission-tomography (PET) with flumazenil is widely used to measure the gamma-aminobutyric-acid (GABAA) receptors in-vivo in humans (Frey et al., 1991, Salmi et al., 2008). Flumazenil (FMZ) binds to the central benzodiazepine receptor (cBZR) which is co-localized with the GABAA receptors on cortical neurons (Frey et al., 1991). Since these receptors are widely expressed on cerebral neurons (Olsen, 1981), PET with FMZ was suggested to be a useful and sensitive marker for the assessment of neural density and integrity (Heiss et al., 1998). In this context, it has been shown that abnormalities of GABAA receptors, as demonstrated with FMZ-PET, were more extensive than the structural abnormalities revealed by magnetic resonance imaging (MRI) in patients with malformations of cortical development and partial seizures (Hammers et al., 2001). In addition, FMZ-binding was found to be decreased in patients with unilateral hippocampal sclerosis that is associated with neuron loss and hippocampal atrophy (Koepp et al., 1997) as well as in irreversibly damaged cortex already early after stroke (Heiss et al., 1998, Heiss et al., 2001, Heiss et al., 2004). Recently, the synthesis of 18F-labelled flumazenil ([18F]FMZ) was reported (Ryzhikov et al., 2005), the use of which is preferable to 11C-labeled flumazenil ([11C]FMZ) due to the longer half-time of the 18F and the higher image quality in terms of spatial resolution due to the shorter positron range of 18F as compared to 11C. Therefore, the combined use of [18F]FMZ and the dedicated high-resolution brain PET scanner HRRT (Siemens Medical Solutions, Knoxville, TN, USA) may offer a PET image with the highest resolution available up to date (FWHM 2.3 mm) and enable an accurate assessment of cortical GABAA receptor density in-vivo.
In this study, we use MRI-based SCT-mapping as a measure of gray matter morphology and high resolution [18F]FMZ-PET as a surrogate marker for neuronal density in-vivo. In combining both methods we seek to answer the question whether the variations in cortical thickness as assessed with MRI are related to variations in neuronal density and if this relationship holds for cortex regions of different cytoarchitectonic type (e.g. homotypical isocortex as well as granular and agranular heterotypical isocortex).
Section snippets
Subjects
10 healthy controls (10 months; age 61 ± 10 years) were investigated at the Brain Imaging Centre of the Montreal Neurological Institute of the McGill University, Montreal, Canada, by means of MRI and PET. All subjects gave their informed, written consent to participate in the study. The protocol was approved by the Ethics Committee of the McGill University, Montreal, Canada.
MR-imaging and cortical thickness generation
In all subjects anatomical T1 weighted MRI sequences were obtained on a Siemens Sonata 1.5 Tesla Scanner (Siemens Medical
Cortical thickness
The averaged magnitude of SCT estimates for the whole cerebral cortex was 3.1 ± 0.37 mm and ranged between 2.7 and 3.8 mm, with significant variations in SCT depending on the localisation of the VOI (Table 2). SCT data analysis revealed the highest magnitudes of SCT the anterior cingulate (3.3 ± 0.21 mm), the temporal cortex (temporo-polar: 3.8 ± 0.18 mm; lateral: 3.3 ± 0.20 mm) as well as the lateral prefrontal cortex (3.3 ± 0.14 mm) as shown in Table 2 and Fig. 1. The lowest values were found in the primary
Cortical thickness
One of the earliest studies, investigating the thickness of the cerebral cortex was that of v. Economo and Koskinas (1925), who provided detailed maps of cortical thickness in human brain, including measurements of the individual cortical layers. They found the average thickness of the cortex to be 3.5 mm, varying by region ranging from 1.5 to 4.5 mm, and furthermore reported variation in thickness within cortical folds. Based on those historical values (which have yet to be re-examined), the
Acknowledgments
This work was supported by a Canadian Institutes of Health Research (CIHR) grant (Nr. MOP8444) to A. Thiel and a research grant from the Natural Sciences and Engineering Council (NCERC) Canada to R. Schirrmacher. C. la Fougère was funded by a grant of the German Research Council (Deutsche Forschungs Gemeinschaft) (Grant Nr LA 2681/1-1) and the Bavarian Research Alliance (BayFOR). The authors would like to thank the research staff of the cyclotron and the PET technicians (McConnell Brain Imaging
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