Isotropic non-white matter partial volume effects in constrained spherical deconvolution.

Impact of hemodynamic effects on diffusion-weighted fMRI signals

Multi-tissue constrained spherical deconvolution for improved analysis of multi-shell diffusion MRI data

Despite the many neuroimaging studies that suggest gray matter volume reductions in schizophrenia, there is no compelling postmortem evidence to suggest neuronal loss, nor is there a distinctive or specific signature of gray matter abnormalities in schizophrenia. Instead, there appears to be no observed focal lesion that characterizes gray matter pathology in schizophrenia. This state of affairs has led to a movement away from conceptualizing schizophrenia as resulting from a single lesion, to conceptualizing schizophrenia as arising from abnormal communication between brain regions. Abnormal connectivity between brain regions is not a new concept, as Bleuler (1911) postulated such abnormalities. What is new, however, is an appreciation that brain regions that are not spatially proximal may be connected functionally into neural networks and that to understand altered neural connectivity we need to have a better understanding of the connections between brain regions which are made possible by white matter, the main infrastructure in the brain that makes possible long distance communication among neurons. Accordingly, a focus on white matter connections in the brain has become increasingly of interest in schizophrenia, particularly in the areas of imaging studies, postmortem studies, and new animal models of schizophrenia. This special issue focuses on schizophrenia and oligodendrocytes, the latter a class of neuroglia that give rise to myelin. The primary aim of this special issue is to understand and to clarify further white matter pathology in schizophrenia and how it may contribute to disconnectivity among brain regions, which results in the observed cognitive, behavioral, and clinical symptoms in this disorder. The first paper begins with a description of the theory that schizophrenia reflects a disorder of connectivity. The proposition put forth is that schizophrenia is, at least in part, the result of abnormal communication between brain regions that may be spatially distant but nonetheless functionally connected. As white matter is the main infrastructure for brain connectivity, this paper focuses on the use of a magnetic resonance imaging (MRI) technique called diffusion tensor imaging (DTI) to gain insight into the role of white matter abnormalities in schizophrenia. This paper also focuses on the functional implications of white matter abnormalities, particularly with regard to the possible role of myelin in modulating the transmission velocity of neural discharges. The paper ends with a speculative hypothesis about the relationship between gray matter and white matter abnormalities in schizophrenia. The second paper also focuses on altered neuronal connectivity. Here, however, the focus is on altered connectivity and impaired myelination in a postmortem study of schizophrenia and normal controls, where electron microscopy is used to study myelinated fibers and oligodendrocytes. This morphometric study examines myelinated fibers in the prefrontal cortex in both gray and white matter. Six types of abnormal fibers and ultrastructural alterations are described in the schizophrenia sample. The study reveals increased pathological fibers in gray matter in both young and elderly patients that are associated with positive symptoms, while in elderly patients, the frequency of pathological fibers in white matter is increased and these changes are associated with more negative symptoms. The key implication here is that altered myelinated fibers in white matter in schizophrenia likely follow alterations of myelinated fibers in gray matter that occur earlier in the course of illness. The third paper is a postmortem study on age-related changes in the number of oligodendrocytes in prefrontal cortex in schizophrenia, bipolar disorder and major depression. The study reveals an age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA9 and 10 that is seen only in normal controls and not in schizophrenia or in mood disorders. The absence of the normal age-related increase in oligodendrocytes in patients suggests that this aspect of normal brain development is dysregulated in schizophrenia and in mood disorders, and confirms postmortem and imaging data, further highlighting the fact that the absence of a normal age-related increase in oligodendrocytes is a key shared feature in these psychiatric populations. The fourth paper reviews white matter abnormalities in schizophrenia, including imaging and postmortem findings on the disconnectivity theory of schizophrenia, a major theme that underlies the three previous papers in this special issue. This paper then reviews some of the white matter diseases that commonly lead to psychotic symptoms and then reviews transgenic and mutant mouse models of schizophrenia. More specifically, genetic mouse models such as Plp1 transgenic mice and mutant mice heterogeneous for either NRG1 or its receptor erbB4, as well as Nogo-A- deficient mice are reviewed. This is followed by a focus on the myelin toxicity model of mice fed cuprizone. In the early stage (the second and third week) of the cuprizone feeding, mice show higher dopamine levels and lower norepinephrine levels in their prefrontal cortex, along with behavioral changes indicative of increased CNS activity. In the late stage (weeks 4–6), when demyelination and oligodendrocyte loss are obvious, mice display cognitive deficits as well as deficits in social interactions that are reminiscent of social withdrawal seen in patients with schizophrenia. Importantly, this cuprizone-feeding mouse may be used as an in vivo platform for psychopharmacological studies testing the effects of antipsychotic drugs on white matter alterations and associated behavioral changes, in addition to providing a new animal model of schizophrenia. The fifth and final paper of this special issue focuses on abnormal behavior and microstructural changes in juvenile mice that are repeatedly exposed to nonneurotoxic levels of amphetamine. These mice are compared with nonamphetamine treated mice. Oligodendrocyte numbers and three proteins expressed in mature oligodendrocytes are investigated in these young male mice at sacrifice. Treated mice showed higher locomotion and impaired spatial working memory, along with lowered Noga-A and GST-pi proteins, and lower MBP proteins, in frontal cortex and hippocampus and fewer mature oligodendrocytes in frontal cortex and corpus callosum, as well as lower MBP staining in frontal cortex, corpus callosum, and hippocampus, than untreated mice. These differences suggest that in wild-type mice late developing white matter is vulnerable to amphetamine and may lead to compromised white matter with increased dopamine in specific brain regions. Not only do these findings explain well the increased locomotion and impaired spatial working memory observed in amphetamine-treated mice, but also may serve as a principle for the amphetamine-treated mouse being used as a novel animal model of schizophrenia. To summarize, compared to the focus on gray matter and neurons, research on white matter and myelin/glial has been sparse in schizophrenia. In this special issue, neuroimaging findings are presented that suggest that myelin abnormalities in schizophrenia may underlie the white matter abnormalities observed using diffusion tensor imaging techniques. Data from postmortem studies also confirm the presence of oligodendrocyte and myelin abnormalities in schizophrenia as well as mood disorders. Oligodendrocytes provide protection and improve communication between brain regions and the oligodendroglia-producing myelin is approaching maturity in the same time frame as the onset of symptoms. Further, normal age-related white matter increases and related gray matter changes that likely predate the white matter changes are dysregulated in schizophrenia and may contribute to the clinical symptomatology of the disease. Finally, the recently developed animal models are not only of help in understanding connectivity abnormalities in schizophrenia but also provide novel platforms to test novel therapeutic approaches for schizophrenic patients. Treatments specifically targeting white matter, for example, may improve on the efficacy of those treatments currently in use. Martha E. Shenton Haiyun Xu Vahram Haroutunian George Bartzokis

Spatial HARDI: Improved visualization of complex white matter architecture with Bayesian spatial regularization

Event Abstract Back to Event Technical and functional validations of High Angular Resolution Diffusion Imaging (HARDI)-MR tractography in paediatric epilepsy patients Sarah M. Barton1*, Joseph Y. Yang2, Wirginia Maixner2, A. Simon Harvey3, 4, Jeremy Freeman3, Richard Beare1, Marc Seal1, 4 and Vicki Anderson4, 5, 6 1 Murdoch Childrens Research Institute, Developmental Imaging, Australia 2 The Royal Children’s Hospital, Department of Neurosurgery, Australia 3 The Royal Children’s Hospital, Department of Neurology, Australia 4 The University of Melbourne, Department of Paediatrics, Australia 5 Murdoch Childrens Research Institute, Child Neuropsychology, Australia 6 The University of Melbourne, School of Psychological Sciences, Australia Background: HARDI-MR tractography is a neuroimaging technique that allows modelling of white matter tracts in the brain. The ability to visualise white matter tracts pre-operatively has the potential to improve neurosurgery accuracy and outcome. However despite its growing popularity, questions remain regarding its technical reproducibility and validity in routine clinical use. Here we examine the reliability of a locally practised HARDI-MR tractography method in paediatric epilepsy patients and in a novel demonstration present the functional validation of the technique against multimodal clinical investigations. Methods: Eight patients were identified retrospectively from our Children’s Epilepsy Program database. All cases had pre-operative diffusion MRI sequences and motor and/or language functional MRI (fMRI). In select cases, intra- or extra-operative motor and/or language cortical mapping results were available. Corticospinal (CST) and superior longitudinal fasciculus (SLF) tracts were generated by two different operators. Coefficients of variation (CV), intra-class correlation coefficients (ICC) and dice similarity coefficients (DSC) were calculated to assess reproducibility of tract metrics and degree of tract overlap between the operators. Tractography results were compared to fMRI activation, cortical mapping results and the patient’s clinical assessment findings. Results: All white matter tracts generated were visually comparable between operators. The tract measures showed low CV values, high ICC values and high DSC scores, indicating there was a high degree of reproducibility and overlap within and between the two operators. Cortical origin and terminations of all CST and SLF tracts matched with the patient’s areas of motor or language fMRI activation. In all but one case, tractography results matched cortical stimulation findings. Tracts were also compatible with the clinical assessment findings. Discussion: In a group of paediatric epilepsy patients, tractography results could be reliably generated and reproduced. In a novel demonstration, there was correspondence between the anatomical course of the tracts with areas of fMRI activation and, in all but one case, cortical stimulation findings. This suggests that in experienced hands, HARDI-MR tractography can be a reliable and valid technique in clinical settings. HARDI-MR tractography has the potential to make valuable contributions to neurosurgery planning to improve outcome for patients. Keywords: tractography, corticospinal tract, Superior longitudinal fasciculus, Paediatric, Epilepsy, Neurosurgery, diffusion imaging Conference: ACNS-2013 Australasian Cognitive Neuroscience Society Conference, Clayton, Melbourne, Australia, 28 Nov - 1 Dec, 2013. Presentation Type: Poster Topic: Other Citation: Barton SM, Yang JY, Maixner W, Harvey A, Freeman J, Beare R, Seal M and Anderson V (2013). Technical and functional validations of High Angular Resolution Diffusion Imaging (HARDI)-MR tractography in paediatric epilepsy patients. Conference Abstract: ACNS-2013 Australasian Cognitive Neuroscience Society Conference. doi: 10.3389/conf.fnhum.2013.212.00059 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 Oct 2013; Published Online: 25 Nov 2013. * Correspondence: Dr. Sarah M Barton, Murdoch Childrens Research Institute, Developmental Imaging, Parkville, Victoria, Australia, sarah.barton@mcri.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sarah M Barton Joseph Y Yang Wirginia Maixner A. Simon Harvey Jeremy Freeman Richard Beare Marc Seal Vicki Anderson Google Sarah M Barton Joseph Y Yang Wirginia Maixner A. Simon Harvey Jeremy Freeman Richard Beare Marc Seal Vicki Anderson Google Scholar Sarah M Barton Joseph Y Yang Wirginia Maixner A. Simon Harvey Jeremy Freeman Richard Beare Marc Seal Vicki Anderson PubMed Sarah M Barton Joseph Y Yang Wirginia Maixner A. Simon Harvey Jeremy Freeman Richard Beare Marc Seal Vicki Anderson Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The correct interpretation of clinical positron emission tomography (PET) data depends largely on the physical limits of the PET scanner. The partial volume effect (PVE) is related to the size of the studied object compared to the spatial resolution. It represents one of the most important limiting factors in quantitative data analysis. This effect is increased in the case of atrophy, as in patients with Alzheimer disease (AD), and it influences measurement of the metabolic reduction generally seen in cerebral degeneration. In this case, interpretation can be biased, because cortical activity will be underestimated due to the atrophy. In general, anatomical images of AD patients have shown diffuse atrophy, while PET studies have found widespread hypometabolism affecting the parietal and temporal lobes. Although hypometabolic areas usually correspond to atrophic regions, they also occur without such changes. Thus, the aim is to differentiate authentic hypometabolism (decrease of glucose consumption per unit volume of gray matter) from that due to PVE from atrophy (cell loss). Consequently, we are using a method for three-dimensional (3D) correction of human PET data with 3D magnetic resonance imaging (MRI). We measured atrophy and metabolism by using both T1-weighted MR images and high and medium resolution PET scans. We injected 12 patients and controls with [18F]fluorodeoxyglucose for glucose consumption measurements. Atrophy was estimated in the following way. We isolated the cerebral structures, using a segmentation technique on the MRI scans, into gray matter (GM), white matter, and cerebrospinal fluid. We superimposed the PET images onto the MR images to obtain anatomo-functional correlations. We degraded the segmented MR images to the resolution of the PET images by a convolution process to create a PET image correction map. We corrected the metabolic PET data for the PVE. We studied the cerebral metabolic rate of glucose in the GM where metabolic variation is the most relevant to AD. By dealing with problems relating to the sensitivity to the segmentation and to the PET-MRI coregistration, computation of MRI convolution processes provided the degree of PVE on a pixel-by-pixel basis, allowing correction of hypometabolisms contained in GM PET values. Global cortical metabolism increased after correction for PVE by, on average, 29 and 24% for tomographs acquired with medium (TTV03 LETI) and high (ECAT 953B CTI/Siemens) resolution, respectively, whereas the cortical metabolism increased by 75 and 65% for the respective tomographs in AD patients. The difference of metabolism between scans after correction for PVE was less than before correction, decreasing from 31 to 17%. This difference was most marked in the frontal and temporal lobes. Fusion imaging allowed correction for PVE in metabolic data using 3D MRI and determination of whether a change in the apparent radiotracer concentration in PET data reflected an alteration in GM volume, a change in radiotracer concentration per unit volume of GM, or both.

Structural MRI findings of abnormalities in the prefrontal cortex in schizophrenia and affective disorder have been inconsistent likely due to small, heterogeneous samples, the evaluation of prefrontal gray and white matter combined, and the fact that prefrontal cortex is typically not delineated into separate gyri (e.g., Shenton et al., 2001; Strakowski et al., 2002). We previously reported smaller prefrontal gray matter in first-episode schizophrenia relative to first-episode affective psychosis and controls (Hirayasu et al., 2001). One unresolved question in the literature is whether or not further volume reduction will be observed over time, the focus of this report. Prefrontal gray and white matter volumes were measured (see Fig. 1) in patients at the time of first hospitalization for schizophrenia (n=12, 3 females) or affective psychosis (n=10, 1 female, 9 bipolar, 1 unipolar), and psychiatrically well subjects (n=15, 1 female). Subjects were rescanned approximately 1.5 years later. Seven schizophrenia, six affective, and four comparison subjects were previously described solely at first scan (Hirayasu et al., 2001). Samples did not differ in age (28.1±8.4; 22.9±2.8; 25.4±4.5; F(2,34)=2.2, p=0.12) or WAIS Information scores (11.8±3.4; 12.2±3.1, 11.8±2.0; F(2.32)=0.6, p=0.9), nor in parental socioeconomic status (F(2.34)=2.32, p=0.11) or handedness (F(2.33)=1.6, p=0.22). BPRS scores were higher in schizophrenics (41.2±13.2) than affectives (33.8±8.0) (F(1,20)=5.71, p=0.027). Similar neuroleptics were prescribed for the patient groups (schizophrenics: 7 typical, 4 atypical, 1 none; affectives: 6 typical, 3 atypical, 1 none). Fig. 1 Prefrontal ROI definitions and volumes. (a) Coronal slice, (b) axial slice showing prefrontal gray and white matter, and (c) three. Three-dimensional reconstruction of the extent of gray and white matter boundaries. MR images were acquired with a 1.5-T ... Relative volumes [i.e., absolute volumes divided by intracranial contents (ICC)] were used in the analyses. Repeated-measures ANOVA was performed with diagnosis as the between-subjects factor and time and side as the within-subjects factors for gray and white matter separately. Prefrontal gray matter at time 1 was significantly different among groups (F2,30=5.56, p=0.009), with schizophrenics smaller than controls and affectives, who did not differ from each other. There was no interaction for group by time by side for prefrontal gray matter (F2,34=0.65, p=0.53). All groups showed larger gray matter on the left (F2,30=8.72, p=0.006). White matter volumes did not differ among groups (p>0.87), and all groups showed more white matter on the right (F1,30=39.20, p<0.001) and a reduction over time (F1,30=10.902, p=0.002), there was a trend for this effect to be larger on the right (F1,30=3.14, p=0.086) (%change over time for right white matter: schizophrenics 2.8%; affectives 6.5%; controls 2.1%). Neither removing the unipolar depression subject nor removing the females altered the results. There was no significant correlation between ROI volume change and medication dosage at time 1 for either patient group (Time 2 data came from out patients based on self-report and was for this reason not used). These data suggest that prefrontal cortical gray matter is selectively smaller at first hospitalization for schizophrenia relative to affective psychosis and controls, but this volume difference did not change over the relatively short post-first hospitalization time examined. Small gray matter volumes may be due to reduced dendritic arborization or increased neural density in prefrontal cortex in schizophrenia (Benes et al., 1992; Selemon et al., 1998). White matter, which was not different among groups, showed a decline with time in all groups, possibly consistent with normal aging (Good et al., 2001, although Bartzokis et al., 2001). Potential reasons for our not observing selective gray matter reductions point to several limitations of this study including the gender distribution, as females may have greater dorsolateral and orbitofrontal lobe involvement and males greater dorsomedial changes in schizophrenia (Gur et al., 2000); the use of large ROI, as sub-regions within the prefrontal cortex may change in volume at different rates (Gur et al., 1998; DeLisi et al., 1997); and lack of exact medication dosages and compliance histories during the intrascan interval cannot be ruled out as possible confounds. Although the sample size was small, the effect size was also small (Fig. 1) suggesting that even enlarging the sample would not result in a significant change in volume over time for either gray or white matter.

Limited spatial resolution of positron emission tomography (PET) can cause significant underestimation in the observed regional radioactivity concentration (so-called partial volume effect or PVE) resulting in systematic errors in estimating quantitative physiologic parameters. The authors have formulated four mathematical models that describe the dynamic behavior of a freely diffusible tracer (H215O) in a region of interest (ROI) incorporating estimates of regional tissue flow that are independent of PVE. The current study was intended to evaluate the feasibility of these models and to establish a methodology to accurately quantify regional cerebral blood flow (CBF) corrected for PVE in cortical gray matter regions. Five monkeys were studied with PET after IV H2(15)O two times (n = 3) or three times (n = 2) in a row. Two ROIs were drawn on structural magnetic resonance imaging (MRI) scans and projected onto the PET images in which regional CBF values and the water perfusable tissue fraction for the cortical gray matter tissue (hence the volume of gray matter) were estimated. After the PET study, the animals were killed and stereologic analysis was performed to assess the gray matter mass in the corresponding ROIs. Reproducibility of the estimated parameters and sensitivity to various error sources were also evaluated. All models tested in the current study yielded PVE-corrected regional CBF values (approximately 0.8 mL x min(-1) x g(-1) for models with a term for gray matter tissue and 0.5 mL x min(-1) x g(-1) for models with a term for a mixture of gray matter and white matter tissues). These values were greater than those obtained from ROIs tracing the gray matter cortex using conventional H2(15)O autoradiography (approximately 0.40 mL x min(-1) x g(-1)). Among the four models, configurations that included two parallel tissue compartments demonstrated better results with regards to the agreement of tissue time-activity curve and the Akaike's Information Criteria. Error sensitivity analysis suggested the model that fits three parameters of the gray matter CBF, the gray matter fraction, and the white matter fraction with fixed white matter CBF as the most reliable and suitable for estimating the gray matter CBF. Reproducibility with this model was 11% for estimating the gray matter CBF. The volume of gray matter tissue can also be estimated using this model and was significantly correlated with the results from the stereologic analysis. However, values were significantly smaller compared with those measured by stereologic analysis by 40%, which can not be explained by the methodologic errors. In conclusion, the partial volume correction was essential in quantitation of regional CBF. The method presented in this article provided the PVE-corrected regional CBF in the cortical gray matter tissue. This study also suggests that further studies are required before using MRI derived anatomic information for PVE correction in PET.

Differentiation of absolute metabolite concentrations between gray and white matter in the occipital region of normal human brain was performed by in vivo localized single-voxel 1H magnetic resonance spectroscopy at 1.5 Tesla with long echo time (136 ms). With the combination of image segmentation between white and gray matter and cerebrospinal fluid, signal compensation of T1 and T2 effects, tissue water signal as the internal concentration reference, as well as compensation by different water contents in gray and white matters, it was determined that the levels of N-acetylaspartate (NAA), creatine and/or phosphocreatine (Cr), and choline-containing compounds (Cho) in gray matter were significantly higher than in white matter. The averaged NAA, Cr, and Cho concentrations in gray matter were 11.0, 9.7, and 1.9 mM/liter, respectively, in comparison with 7.5, 5.2, and 1.6 mM/liter in white matter. These results suggest that precise composition of white and gray matter and cerebrospinal fluid is necessary to avoid partial voluming effect in a single voxel and to accurately quantify the metabolite concentrations.

Fusion of white and gray matter geometry: a framework for investigating brain development.

Schizophrenia has been characterized as a neurodevelopmental disorder, with structural brain abnormalities reported at all stages. However, at present, it remains unclear whether gray and white matter abnormalities represent related or independent pathologies in schizophrenia. In this study, we present findings from an integrative analysis exploring the morphological relationship between gray and white matter in 45 schizophrenia participants and 49 healthy controls. We utilized mutual information (MI), a measure of how much information two variables share, to assess the morphological dependence between gray and white matter in three segments of the corpus callsoum, and the gray matter regions these segments connect: (1) the genu and the left and right rostral middle frontal gyrus (rMFG), (2) the isthmus and the left and right superior temporal gyrus (STG), (3) the splenium and the left and right lateral occipital gyrus (LOG). We report significantly reduced MI between white matter tract dispersion of the right hemispheric callosal connections to the STG and both cortical thickness and area in the right STG in schizophrenia patients, despite a lack of group differences in cortical thickness, surface area, or dispersion. We believe that this reduction in morphological dependence between gray and white matter may reflect a possible decoupling of the developmental processes that shape morphological features of white and gray matter early in life. The present study also demonstrates the importance of studying the relationship between gray and white matter measures, as opposed to restricting analyses to gray and white matter measures independently.

MRI diffusion-weighted imaging of the brain: Contributions to image contrast from CSF signal reduction, use of a long echo time and diffusion effects

We consider the problem of tracking white matter fibers in high angular resolution diffusion imaging (HARDI) data while simultaneously estimating the local fiber orientation profile. Prior work showed that an unscented Kalman filter (UKF) can be used for this problem, yet existing algorithms employ parametric mixture models to represent water diffusion and to define the state space. To address this restrictive model dependency, we propose to extend the UKF to HARDI data modeled by orientation distribution functions (ODFs), a more generic diffusion model. We consider the spherical harmonic representation of the HARDI signal as the state, enforce nonnegativity of the ODFs, and perform tractography using the directions at which the ODFs attain their peaks. In simulations, our method outperforms filtered two-tensor tractography at different levels of noise by achieving a reduction in mean Chamfer error of 0.05 to 0.27 voxels; it also produced in vivo fiber tracking that is consistent with the neuroanatomy.

Apolipoprotein E (apoE) and cholesterol play a critical role in synapse and myelin maintenance and integrity and are thus appealing candidates in the pathogenesis of schizophrenia and bipolar disorder. To explore the role of these 2 molecules, we quantified cholesterol and apoE levels in prefrontal grey and white matter in patients with schizophrenia, bipolar disorder and healthy controls. Furthermore, we investigated the relations between apoE and cholesterol levels and the APOE genotype. We obtained dorsolateral prefrontal grey and white matter from the Stanley Medical Research Institute Brain Collection (schizophrenia n = 35, bipolar disorder n = 35 and controls n = 35). Cholesterol levels were quantified using high-pressure liquid chromatography, whereas apoE was measured by enzyme-linked immunosorbent assay. We found no significant differences in cholesterol or apoE levels among the groups. ApoE levels were higher in grey matter than in white matter in all groups; conversely, levels of cholesterol were higher in white matter than in grey matter. We observed a significant inverse correlation between apoE and cholesterol levels in both grey and white matter. Furthermore, in grey matter, apoE levels were significantly higher in APOE ε2 carriers compared with APOE ε3 or APOE ε4 carriers, with cholesterol levels following the opposite trend. LIMITATIONS of our study include our inability to control for potential confounding variables and the small numbers of APOE ε2 and ε4 carriers in each group. Although large amounts of cholesterol are present in white matter, apoE expression is limited. The APOE genotype may play a role in the regulation of both cholesterol and apoE levels in grey matter. The impact of APOE polymorphisms on lipid homeostasis in people with psychiatric disorders warrants further investigation.

BackgroundMK6240 and Flortaucipir (FTP) are tau PET tracers with differing off‐target signal. Due to partial volume effects (PVE), this off‐target may spill into neighboring cortical regions. We applied different partial volume correction (PVC) methods to MK6240 and FTP images acquired in the same participants within two months to evaluate the performance of the methods within and between tracers.Method15 subjects (Table1) were scanned using MK6240 (SUVR calculated 70‐90min and 90‐110min) and FTP (80‐100min) on a Siemens Biograph mCT and smoothed to 8mm3 resolution. T1 MRIs were segmented using FreeSurfer 7.1. Five different PVC methods were tested: 2 compartment, 3 compartment, Van‐Cittert (VC), geometric transfer matrix (GTM) and region‐based voxelwise (RBV). Different ROI configurations were used when applying GTM/RBV. To determine how well the PVCed data fit the original data, PVCed images were smoothed back to the 8mm3 resolution and compared to the original image within SPM‐segmented gray matter, white matter, CSF, skull and meninges (Figure1).ResultVC fit the original data best after smoothing (Figure2), but had the highest correlation with the original data (Figure3c), meaning VC does not correct the data as much as the other methods and therefore does not address the PVE issue. 2 and 3 compartment fit the gray and white matter well (Figure2) while showing low R2 between the original and PVC data (Figure3). However, these methods assume zero signal outside the cortex, resulting in poor fit of extracortical areas and leading to over‐amplification of the cortical signal. GTM and RBV perform well for both tracers in all 5 regions. Their correlations between original and PVC data are between 2/3 compartment and VC, indicating these methods correct the data. PVC improves the correlation between FTP and MK6240; the highest correlation between tracers is achieved when the same PVC method is applied to both tracers (r2=0.9 for 2 and 3 compartment, r2=0.89 for GTM, r2=0.88 for RBV, r2=0.84 for VC, r2=0.80 for original).ConclusionGTM/RBV assume non‐zero signal outside the cortex resulting in a better fit of the original data, correct the data more than VC, and improve the correlation between MK6240 and FTP.