Publications by authors named "Paul Cumming"

197 Publications

Functional Analysis of Brain Imaging Suggests Changes in the Availability of mGluR5 and Altered Connectivity in the Cerebral Cortex of Long-Term Abstaining Males with Alcohol Dependence: A Preliminary Study.

Life (Basel) 2021 May 30;11(6). Epub 2021 May 30.

Neuroscience Research Institute, Gachon University, Incheon 21565, Korea.

Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration: six months) and ten healthy male controls underwent [C]ABP688 PET imaging and 3-Tesla MRI. For mGluR5 availability, binding potential (BP) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [C]ABP688 BP in the middle temporal and inferior parietal cortices, and higher BP in the superior temporal cortex in the alcohol dependence group compared with controls. Functional connectivity analysis of the rs-fMRI data employed seed regions identified from the quantitative [C]ABP688 PET analysis, which revealed significantly altered functional connectivity from the inferior parietal cortex seed to the occipital pole and dorsal visual cortex in the alcohol dependence group compared with the control group. To our knowledge, this is the first report on the combined analysis of mGluR5 PET imaging and rs-fMRI in subjects with alcohol dependence. These preliminary results suggest the possibility of region-specific alterations of mGluR5 availability in vivo and related functional connectivity perturbations in prolonged abstinent subjects.
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http://dx.doi.org/10.3390/life11060506DOI Listing
May 2021

A binge high sucrose diet provokes systemic and cerebral inflammation in rats without inducing obesity.

Sci Rep 2021 May 27;11(1):11252. Epub 2021 May 27.

Department of Nuclear Medicine, Inselspital, Bern University, Bern, Switzerland.

While the dire cardiometabolic consequences of the hypercaloric modern 'Western' diet are well known, there is not much information on the health impact of a high sucrose diet not inducing weight gain. Here, we tested the hypothesis that rats reared with intermittent binge access to sucrose in addition to normal chow would develop an inflammatory response in brain. To test this hypothesis, we undertook serial PET/MRI scans with the TSPO ligand [F]DPA714 in a group of (n=9) rats at baseline and again after voluntarily consuming 5% sucrose solution three days a week for three months. Compared to a control group fed with normal chow (n=9), the sucrose rats indeed showed widespread increases in the availability of cerebral binding sites for the microglial marker, despite normal weight gain compared to the control diet group. Subsequent immunofluorescence staining of the brains confirmed the PET findings, showing a widespread 20% increase in the abundance of IBA-1-positive microglia with characteristic 'semi-activated' morphology in the binge sucrose rats, which had 23% lower density of microglial endpoints and 25% lower mean process length compared to microglia in the control rats with ordinary feeding. GFAP immunofluorescence showed no difference in astroglial coverage in the sucrose rats, except for a slight reduction in hypothalamus. The binge sucrose diet-induced neuroinflammation was associated with a significant elevation of white blood cell counts. Taking these results together, we find that long-term intake of sucrose in a binge paradigm, similar in sucrose content to the contemporary Western diet, triggered a low-grade systemic and central inflammation in non-obese rats. The molecular mechanism of this phenomenon remains to be established.
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http://dx.doi.org/10.1038/s41598-021-90817-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160215PMC
May 2021

Glitter in the Darkness? Non-fibrillar β-amyloid Plaque Components Significantly Impact the β-amyloid PET Signal in Mouse Models of Alzheimer's Disease.

J Nucl Med 2021 May 20. Epub 2021 May 20.

University Hospital of Munich, LMU Munich, Germany.

β-amyloid PET (Aβ-PET) is an important tool for quantification of amyloidosis in the brain of suspected Alzheimer's disease (AD) patients and transgenic AD mouse models. Despite the excellent correlation of Aβ-PET with gold standard immunohistochemical assessments, the relative contributions of fibrillar and non-fibrillar Aβ components to the in vivo Aβ-PET signal remain unclear. Thus, we obtained two murine cerebral amyloidosis models that present with distinct Aβ plaque compositions and performed regression analysis between immunohistochemistry and Aβ PET to determine the biochemical contributions to Aβ-PET signal in vivo. We investigated groups of AppNL-G-F and APPPS1 mice at three, six and 12 months of age by longitudinal F-florbetaben Aβ-PET and with immunohistochemical analysis of the fibrillar and total Aβ burdens. We then applied group level inter-modality regression models using age and genotype matched sets of fibrillar/ non-fibrillar Aβ data (predictors) and Aβ-PET results (outcome) for both transgenic models. An independent group of double-hit APPPS1 mice with dysfunctional microglia due to knock-out of triggering receptor expression on myeloid cells 2 (Trem2-/-) served for validation and evaluation of translational impact. Neither fibrillar nor non-fibrillar Aβ content alone sufficed to explain the Aβ-PET findings in either transgenic AD model. However, a regression model compiling fibrillar and non-fibrillar Aβ together with the estimate of individual heterogeneity and age at scanning could explain a 93% of variance of the Aβ-PET signal (P<0.001). Fibrillar Aβ burden had a 16-fold higher contribution to the Aβ-PET signal when compared to non-fibrillar Aβ. However, given the relatively greater abundance of non-fibrillar Aβ, we estimate that non-fibrillar Aβ produced 79±25% of the net in vivo Aβ-PET signal in AppNL-G-F mice, and 25±12% in the APPPS1 mice. Corresponding results in separate groups of APPPS1/Trem2-/- and APPPS1/Trem2+/+ mice validated the calculated regression factors and revealed that the altered fibrillarity due to Trem2 knockout impacts the Aβ-PET signal. Taken together, the in vivo Aβ-PET signal derives from the composite of fibrillar and non-fibrillar Aβ plaque components. While fibrillar Aβ has inherently higher PET tracer binding, the greater abundance of non-fibrillar Aβ plaque in AD model mice contributes importantly to the PET signal.
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http://dx.doi.org/10.2967/jnumed.120.261858DOI Listing
May 2021

White-matter alterations are associated with cognitive dysfunction decades following moderate-to-severe traumatic brain injury and/or post-traumatic stress disorder.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 May 3. Epub 2021 May 3.

Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address:

Background: Possible white matter (WM) alterations following moderate-to-severe TBI and post-traumatic stress disorder (PTSD) and their relationship to clinical outcome have yet to be investigated decades post trauma. We utilized structural MRI and diffusion tensor images to investigate brain volume and WM alterations in Vietnam War veterans with moderate-severe TBI and/or PTSD examined five decades post-trauma.

Methods: Data from 160 veterans with history of moderate-to-severe TBI (n = 23), TBI+PTSD (n = 36), PTSD (n = 53), and control veterans (n = 48) were obtained from the Department of Defense Alzheimer's Disease Neuroimaging Initiative database. Voxel-based morphometry and tract-based spatial statistics were used to investigate ongoing brain morphometry and WM abnormalities. The fractional anisotropy (FA) and mean diffusivity were then correlated with neuropsychological scores and amyloid deposition in the trauma groups.

Results: Compared to controls, the three trauma groups showed grey-matter atrophy, lower FA, and distinctly higher diffusivity in the major WM tracts included the corpus callosum, external and internal capsules, cingulum, inferior and superior longitudinal fasciculi. The FA and mean diffusivity correlated with the cognitive deficits in the trauma groups. Furthermore, the FA in the cingulum correlated negatively with amyloid deposition in the posterior cingulate cortex of all three trauma groups.

Conclusion: DTI detected WM abnormalities that correlated with the severity of present cognitive dysfunction and the degree of cortical amyloid deposition decades following moderate-to-severe TBI and/or PTSD. These results may hint that PTSD secondary to TBI may incur late cognitive sequalae and persistence of brain microstructures alterations.
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http://dx.doi.org/10.1016/j.bpsc.2021.04.014DOI Listing
May 2021

Working memory task induced neural activation: A simultaneous PET/fMRI study.

Neuroimage 2021 May 2;237:118131. Epub 2021 May 2.

Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany; TUM-Neuroimaging Center (TUM-NIC), Technical University of Munich, Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-Universität, Martinsried, Germany.

Purpose: Positron emission tomography (PET) with [F]fluorodeoxyglucose (FDG) is a powerful method for mapping cerebral glucose metabolism as a proxy of neural activity, assuming a steady-state during the recording interval. We asked if a clinical FDG-PET imaging protocol might also capture changes in neural activity associated with performance of a working memory (WM) task.

Methods: To test this concept, we examined hybrid PET/MR data for FDG-PET and simultaneous functional magnetic resonance imaging (fMRI) in a sample of healthy volunteers. The PET image acquisition started 30 min after a bolus injection of approximately 100 MBq FDG, and the WM task was undertaken starting at approximately 60 min post-injection. We reconstructed FDG-PET sum images corresponding to baseline (44-60 min p.i.) and WM tasks (63- 71 min p.i.), each with intensity scaling to the corresponding global mean.

Results: Compared to the baseline resting condition, relative FDG uptake increased during WM task performance in brain regions previously associated with WM. Furthermore, these metabolically active regions partly overlapped with the regions showing task-dependent increases in BOLD signal in simultaneous fMRI.

Conclusion: We find evidence for WM task-induced neural activation using a clinical FDG-PET imaging protocol. These findings encourage the development of dedicated protocols for tracking neural correlates of cognitive function.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118131DOI Listing
May 2021

A comprehensive review of imaging findings in COVID-19 - status in early 2021.

Eur J Nucl Med Mol Imaging 2021 May 1. Epub 2021 May 1.

Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Medical imaging methods are assuming a greater role in the workup of patients with COVID-19, mainly in relation to the primary manifestation of pulmonary disease and the tissue distribution of the angiotensin-converting-enzyme 2 (ACE 2) receptor. However, the field is so new that no consensus view has emerged guiding clinical decisions to employ imaging procedures such as radiography, computer tomography (CT), positron emission tomography (PET), and magnetic resonance imaging, and in what measure the risk of exposure of staff to possible infection could be justified by the knowledge gained. The insensitivity of current RT-PCR methods for positive diagnosis is part of the rationale for resorting to imaging procedures. While CT is more sensitive than genetic testing in hospitalized patients, positive findings of ground glass opacities depend on the disease stage. There is sparse reporting on PET/CT with [F]-FDG in COVID-19, but available results are congruent with the earlier literature on viral pneumonias. There is a high incidence of cerebral findings in COVID-19, and likewise evidence of gastrointestinal involvement. Artificial intelligence, notably machine learning is emerging as an effective method for diagnostic image analysis, with performance in the discriminative diagnosis of diagnosis of COVID-19 pneumonia comparable to that of human practitioners.
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http://dx.doi.org/10.1007/s00259-021-05375-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087891PMC
May 2021

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans.

Molecules 2021 Apr 22;26(9). Epub 2021 Apr 22.

Department of Psychology, University of Fribourg, CH-1700 Fribourg, Switzerland.

Hallucinogens are a loosely defined group of compounds including LSD, -dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with -([C]-methyl)-2-bromo-LSD ([C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [C]-MBL specific binding was to serotonin 5-HT receptors. However, interactions at serotonin 5HT and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood-brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT agonist -(2[CHO]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([O]-water) or metabolism ([F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research.
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http://dx.doi.org/10.3390/molecules26092451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122807PMC
April 2021

Association between age of cannabis initiation and gray matter covariance networks in recent onset psychosis.

Neuropsychopharmacology 2021 Jul 3;46(8):1484-1493. Epub 2021 Mar 3.

Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.

Cannabis use during adolescence is associated with an increased risk of developing psychosis. According to a current hypothesis, this results from detrimental effects of early cannabis use on brain maturation during this vulnerable period. However, studies investigating the interaction between early cannabis use and brain structural alterations hitherto reported inconclusive findings. We investigated effects of age of cannabis initiation on psychosis using data from the multicentric Personalized Prognostic Tools for Early Psychosis Management (PRONIA) and the Cannabis Induced Psychosis (CIP) studies, yielding a total sample of 102 clinically-relevant cannabis users with recent onset psychosis. GM covariance underlies shared maturational processes. Therefore, we performed source-based morphometry analysis with spatial constraints on structural brain networks showing significant alterations in schizophrenia in a previous multisite study, thus testing associations of these networks with the age of cannabis initiation and with confounding factors. Earlier cannabis initiation was associated with more severe positive symptoms in our cohort. Greater gray matter volume (GMV) in the previously identified cerebellar schizophrenia-related network had a significant association with early cannabis use, independent of several possibly confounding factors. Moreover, GMV in the cerebellar network was associated with lower volume in another network previously associated with schizophrenia, comprising the insula, superior temporal, and inferior frontal gyrus. These findings are in line with previous investigations in healthy cannabis users, and suggest that early initiation of cannabis perturbs the developmental trajectory of certain structural brain networks in a manner imparting risk for psychosis later in life.
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http://dx.doi.org/10.1038/s41386-021-00977-9DOI Listing
July 2021

Preclinical Evaluation of [F]FACH in Healthy Mice and Piglets: An F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET.

Int J Mol Sci 2021 Feb 6;22(4). Epub 2021 Feb 6.

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04308 Leipzig, Saxony, Germany.

The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [F]FACH in healthy mice and piglets. We measured the [F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a of 118 ± 12 nM and of 6.0 pmol/mg wet weight. The specificity of [F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC after pre-treatment with α-CCA-Na in mice (-47%) and in piglets (-66%). [F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [F]FACH binding potential (BP) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [F]FACH uptake was confirmed by displacement studies in 4T1 cells. [F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models.
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http://dx.doi.org/10.3390/ijms22041645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915902PMC
February 2021

Serotonin and amyloid deposition: A link between depression and Alzheimer's disease?: An Editorial Highlight on "Pimavanserin, a 5HT receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer's disease" on page 658.

J Neurochem 2021 03 18;156(5):560-562. Epub 2021 Jan 18.

Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland.

Indirect agonism has been invoked as part of the mechanism of antipsychotic action at dopamine D receptors, and more recently as a salient neuropharmacological aspect of the serotonin 5-HT drug pimavanserin (Pim). We now comment on an article in this volume showing that Pim treatment attenuates the deposition of Aβ protein in brain of transgenic Alzheimer's disease model mice. Pim treatment may interfere with Aβ deposition by shifting the balance between two 5-HT signaling pathways, that is, antagonism of G signaling and agonism of G signaling. Treatment with serotonin-selective reuptake inhibitors (SSRIs) evoked also reduced amyloid deposition in transgenic mice, but SSRI treatment does not unequivocally interfere in the progression of human Alzheimer's disease, perhaps because of complex effects of chronic SSRI treatment on multiple serotonin receptor types. Preclinical findings suggest Pim as a promising pharmacological strategy for intervening against Alzheimer's pathology, perhaps at a very early stage of the disease. However, much remains to be learned about the convergence of various receptor-mediated signaling pathways on the final common path leading to net Aβ deposition.
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http://dx.doi.org/10.1111/jnc.15269DOI Listing
March 2021

Microglial activation in the right amygdala-entorhinal-hippocampal complex is associated with preserved spatial learning in App mice.

Neuroimage 2021 04 29;230:117707. Epub 2020 Dec 29.

Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address:

Background: In Alzheimer`s disease (AD), regional heterogeneity of β-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in β-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo.

Methods: In 30 App mice (15 female, 15 male) we acquired cross-sectional 18 kDa translocator protein (TSPO-PET, F-GE-180) and β-amyloid-PET (F-florbetaben) scans at ten months of age. Control data were obtained from age- and sex-matched C57BI/6 wild-type mice. We assessed spatial learning (i.e. Morris water maze) within two weeks of PET scanning and correlated the principal component of spatial learning performance scores with voxel-wise β-amyloid and TSPO tracer uptake maps in App mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance.

Results: Voxel-wise analyses in App mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (β = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning.

Conclusion: Elevated microglial activation in the right amygdala-entorhinal-hippocampal complex of App mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117707DOI Listing
April 2021

Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases.

J Neuroinflammation 2020 Dec 14;17(1):374. Epub 2020 Dec 14.

Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Marchioninstraße 15, 81377, Munich, Germany.

Background: In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls.

Methods: TSPO-PET (F-GE-180) data of C57Bl/6 (wild-type), App (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The App group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry.

Results: Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction (T = - 4.171, p < 0.001). The Aβ model App mice also showed a significant sex × age interaction (T = - 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female App mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same App mice indicated no significant sex × age interaction (T = 0.425, p = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction (T = - 0.671, p = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry.

Conclusion: Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies.
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http://dx.doi.org/10.1186/s12974-020-02046-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737385PMC
December 2020

Molecular imaging of schizophrenia: Neurochemical findings in a heterogeneous and evolving disorder.

Behav Brain Res 2021 02 13;398:113004. Epub 2020 Nov 13.

Central Institute of Mental Health, Department of Molecular Neuroimaging, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

The past four decades have seen enormous efforts placed on a search for molecular markers of schizophrenia using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In this narrative review, we cast a broad net to define and summarize what researchers have learned about schizophrenia from molecular imaging studies. Some PET studies of brain energy metabolism with the glucose analogue FDGhave have shown a hypofrontality defect in patients with schizophrenia, but more generally indicate a loss of metabolic coherence between different brain regions. An early finding of significantly increased striatal trapping of the dopamine synthesis tracer FDOPA has survived a meta-analysis of many replications, but the increase is not pathognomonic of the disorder, since one half of patients have entirely normal dopamine synthesis capacity. Similarly, competition SPECT studies show greater basal and amphetamine-evoked dopamine occupancy at post-synaptic dopamine D receptors in patients with schizophrenia, but the difference is likewise not pathognomonic. We thus propose that molecular imaging studies of brain dopamine indicate neurochemical heterogeneity within the diagnostic entity of schizophrenia. Occupancy studies have established the relevant target engagement by antipsychotic medications at dopamine D receptors in living brain. There is evidence for elevated frontal cortical dopamine D receptors, especially in relation to cognitive deficits in schizophrenia. There is a general lack of consistent findings of abnormalities in serotonin markers, but some evidence for decreased levels of nicotinic receptors in patients. There are sparse and somewhat inconsistent findings of reduced binding of muscarinic, glutamate, and opioid receptors ligands, inconsistent findings of microglial activation, and very recently, evidence of globally reduced levels of synaptic proteins in brain of patients. One study reports a decline in histone acetylase binding that is confined to the dorsolateral prefrontal cortex. In most contexts, the phase of the disease and effects of past or present medication can obscure or confound PET and SPECT findings in schizophrenia.
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http://dx.doi.org/10.1016/j.bbr.2020.113004DOI Listing
February 2021

A Review of Molecular Imaging of Glutamate Receptors.

Molecules 2020 Oct 16;25(20). Epub 2020 Oct 16.

Department of Nuclear Medicine, University of Bern, Inselspital, Freiburgstrasse 18, CH-3010 Bern, Switzerland.

Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (-methyl--aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.
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http://dx.doi.org/10.3390/molecules25204749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587586PMC
October 2020

In vivo glucose metabolism and glutamate levels in mGluR5 knockout mice: a multimodal neuroimaging study using [F]FDG microPET and MRS.

EJNMMI Res 2020 Oct 2;10(1):116. Epub 2020 Oct 2.

Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea.

Background: Perturbed functional coupling between the metabotropic glutamate receptor-5 (mGluR5) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory glutamatergic neurotransmission may contribute to the pathophysiology of psychiatric disorders such as schizophrenia. We aimed to establish the functional interaction between mGluR5 and NMDA receptors in brain of mice with genetic ablation of the mGluR5.

Methods: We first measured the brain glutamate levels with magnetic resonance spectroscopy (MRS) in mGluR5 knockout (KO) and wild-type (WT) mice. Then, we assessed brain glucose metabolism with [F]fluorodeoxyglucose ([F]FDG) positron emission tomography before and after the acute administration of an NMDA antagonist, MK-801 (0.5 mg/kg), in the same mGluR5 KO and WT mice.

Results: Between-group comparisons showed no significant differences in [F]FDG standardized uptake values (SUVs) in brain of mGluR5 KO and WT mice at baseline, but widespread reductions in mGluR5 KO mice compared to WT mice after MK-801 administration (p < 0.05). The baseline glutamate levels did not differ significantly between the two groups. However, there were significant negative correlations between baseline prefrontal glutamate levels and regional [F]FDG SUVs in mGluR5 KO mice (p < 0.05), but no such correlations in WT mice. Fisher's Z-transformation analysis revealed significant between-group differences in these correlations (p < 0.05).

Conclusions: This is the first multimodal neuroimaging study in mGluR5 KO mice and the first report on the association between cerebral glucose metabolism and glutamate levels in living rodents. The results indicate that mGluR5 KO mice respond to NMDA antagonism with reduced cerebral glucose metabolism, suggesting that mGluR5 transmission normally moderates the net effects of NMDA receptor antagonism on neuronal activity. The negative correlation between glutamate levels and glucose metabolism in mGluR5 KO mice at baseline may suggest an unmasking of an inhibitory component of the glutamatergic regulation of neuronal energy metabolism.
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http://dx.doi.org/10.1186/s13550-020-00716-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532251PMC
October 2020

Associations of [F]-APN-1607 Tau PET Binding in the Brain of Alzheimer's Disease Patients With Cognition and Glucose Metabolism.

Front Neurosci 2020 30;14:604. Epub 2020 Jun 30.

Department of Nuclear Medicine, University Hospital Bern, Bern, Switzerland.

Molecular imaging of tauopathies is complicated by the differing specificities and off-target binding properties of available radioligands for positron emission tomography (PET). [F]-APN-1607 ([F]-PM-PBB3) is a newly developed PET tracer with promising properties for tau imaging. We aimed to characterize the cerebral binding of [F]-APN-1607 in Alzheimer's disease (AD) patients compared to normal control (NC) subjects. Therefore, we obtained static late frame PET recordings with [F]-APN-1607 and [F]-FDG in patients with a clinical diagnosis of AD group, along with an age-matched NC group ([F]-APN-1607 only). Using statistical parametric mapping (SPM) and volume of interest (VOI) analyses of the reference region normalized standardized uptake value ratio maps, we then tested for group differences and relationships between both PET biomarkers, as well as their associations with clinical general cognition. In the AD group, [F]-APN-1607 binding was elevated in widespread cortical regions ( < 0.001 for VOI analysis, familywise error-corrected < 0.01 for SPM analysis). The regional uptake in AD patients correlated negatively with Mini-Mental State Examination score (frontal lobe: = -0.632, = 0.004; temporal lobe: = -0.593, = 0.008; parietal lobe: = -0.552, = 0.014; insula: = -0.650, = 0.003; cingulum: = -0.665, = 0.002) except occipital lobe ( = -0.417, = 0.076). The hypometabolism to [F]-FDG PET in AD patients also showed negative correlations with regional [F]-APN-1607 binding in some signature areas of AD (temporal lobe: = -0.530, = 0.020; parietal lobe: = -0.637, = 0.003; occipital lobe: = -0.567, = 0.011). In conclusion, our results suggested that [F]-APN-1607 PET sensitively detected tau deposition in AD and that individual tauopathy correlated with impaired cerebral glucose metabolism and cognitive function.
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http://dx.doi.org/10.3389/fnins.2020.00604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338611PMC
June 2020

Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning.

J Neuroinflammation 2020 Jul 13;17(1):208. Epub 2020 Jul 13.

Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, 81377, Munich, Germany.

Background: P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO μPET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism.

Methods: Transgenic P301S (n = 33) and wild-type (n = 18) female mice were imaged by F-GE-180 TSPO μPET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze, F-fluordesoxyglucose (F-FDG) μPET, and AT8 tau immunohistochemistry at 6.3-6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO μPET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-β mouse models.

Results: TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11-23%, all p < 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-β mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3-6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3-6.7 months.

Conclusions: Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by μPET indicates a delayed time course when compared to amyloid-β mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-β mouse models. The contribution of microglial response to pathology accompanying amyloid-β and tau over-expression merits further investigation.
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http://dx.doi.org/10.1186/s12974-020-01883-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358201PMC
July 2020

Characterizing the heterogeneous metabolic progression in idiopathic REM sleep behavior disorder.

Neuroimage Clin 2020 26;27:102294. Epub 2020 May 26.

Department of Nuclear Medicine, University of Bern, Switzerland; Dept. Informatics, Technische Universität München, Munich, Germany.

Objective: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies such as Parkinson's disease (PD). Positron emission tomography (PET) with F-FDG reveals metabolic perturbations, which are scored by spatial covariance analysis. However, the resultant pattern scores do not capture the spatially heterogeneous trajectories of metabolic changes between individual brain regions. Assuming metabolic progression occurs as a continuum from the healthy control (HC) condition to iRBD and then PD, we investigated spatial dynamics of progressively perturbed glucose metabolism in a cross-sectional study.

Methods: 19 iRBD patients, 38 PD patients and 19 HC subjects underwent F-FDG PET. The images were spatially normalized, scaled to the global mean uptake, and automatically parcellated. We contrasted regional metabolism by group, and allocated the inferred progression to one of several possible trajectories. We further investigated the correlations between F-FDG uptake and the disease duration in the iRBD and PD groups, respectively. We also explored relationships between F-FDG uptake and the Unified Parkinson's Disease Rating Scale motor (UPDRS III) scores in the PD group.

Results: PD patients exhibited more extensive relative hyper- and hypo-metabolism than iRBD patients. We identified three dynamic metabolic trajectories, cross-sectional hypo- or hypermetabolism, cross-sectionally unchanged hypo- or hypermetabolism, cross-sectionally late hypo- or hypermetabolism, appearing only in the contrast of PD with iRBD. No correlation was found between relative F-FDG metabolism and disease duration in the iRBD group. Regional hyper- and hypo-metabolism in the PD patients correlated with disease duration or clinical UPDRS III scores.

Conclusion: Cerebral metabolism changes heterogeneously in a continuum extending from HC to iRBD and PD groups in this preliminary study. The distinctive metabolic trajectories point towards a potential neuroimaging biomarker for conversion of iRBD to frank PD, which should be amenable to advanced pattern recognition analysis in future longitudinal studies.
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http://dx.doi.org/10.1016/j.nicl.2020.102294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322340PMC
March 2021

Asymmetry of Fibrillar Plaque Burden in Amyloid Mouse Models.

J Nucl Med 2020 12 15;61(12):1825-1831. Epub 2020 May 15.

Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University Munich, Munich, Germany

Asymmetries of amyloid-β (Aβ) burden are well known in Alzheimer disease (AD) but did not receive attention in Aβ mouse models of Alzheimer disease. Therefore, we investigated Aβ asymmetries in Aβ mouse models examined by Aβ small-animal PET and tested if such asymmetries have an association with microglial activation. We analyzed 523 cross-sectional Aβ PET scans of 5 different Aβ mouse models (APP/PS1, PS2APP, APP-SL70, , and APPswe) together with 136 18-kDa translocator protein (TSPO) PET scans for microglial activation. The asymmetry index (AI) was calculated between tracer uptake in both hemispheres. AIs of Aβ PET were analyzed in correlation with TSPO PET AIs. Extrapolated required sample sizes were compared between analyses of single and combined hemispheres. Relevant asymmetries of Aβ deposition were identified in at least 30% of all investigated mice. There was a significant correlation between AIs of Aβ PET and TSPO PET in 4 investigated Aβ mouse models (APP/PS1: = 0.593, = 0.001; PS2APP: = 0.485, = 0.019; APP-SL70: = 0.410, = 0.037; : = 0.385, = 0.002). Asymmetry was associated with higher variance of tracer uptake in single hemispheres, leading to higher required sample sizes. Asymmetry of fibrillar plaque neuropathology occurs frequently in Aβ mouse models and acts as a potential confounder in experimental designs. Concomitant asymmetry of microglial activation indicates a neuroinflammatory component to hemispheric predominance of fibrillary amyloidosis.
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http://dx.doi.org/10.2967/jnumed.120.242750DOI Listing
December 2020

Towards guidelines to harmonize textural features in PET: Haralick textural features vary with image noise, but exposure-invariant domains enable comparable PET radiomics.

PLoS One 2020 16;15(3):e0229560. Epub 2020 Mar 16.

Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Purpose: Image texture is increasingly used to discriminate tissues and lesions in PET/CT. For quantification or in computer-aided diagnosis, textural feature analysis must produce robust and comparable values. Because statistical feature values depend on image count statistics, we investigated in depth the stability of Haralick features values as functions of acquisition duration, and for common image resolutions and reconstructions.

Methods: A homogeneous cylindrical phantom containing 9.6 kBq/ml Ge-68 was repeatedly imaged on a Siemens Biograph mCT, with acquisition durations ranging from three seconds to three hours. Images with 1.5, 2, and 4 mm isometrically spaced voxels were reconstructed with filtered back-projection (FBP), ordered subset expectation maximization (OSEM), and the Siemens TrueX algorithm. We analysed Haralick features derived from differently quantized (3 to 8-bit) grey level co-occurrence matrices (GLCMs) as functions of exposure E, which we defined as the product of activity concentration in a volume of interest (VOI) and acquisition duration. The VOI was a 50 mm wide cube at the centre of the phantom. Feature stability was defined for df/dE → 0.

Results: The most stable feature values occurred in low resolution FBPs, whereas some feature values from 1.5 mm TrueX reconstructions ranged over two orders of magnitude. Within the same reconstructions, most feature value-exposure curves reached stable plateaus at similar exposures, regardless of GLCM quantization. With 8-bit GLCM, median time to stability was 16 s and 22 s for FBPs, 18 s and 125 s for OSEM, and 23 s, 45 s, and 76 s for PSF reconstructions, with longer durations for higher resolutions. Stable exposures coincided in OSEM and TrueX reconstructions with image noise distributions converging to a Gaussian. In FBP, the occurrence of stable values coincided the disappearance of negatives image values in the VOI.

Conclusions: Haralick feature values depend strongly on exposure, but invariance exists within defined domains of exposure. Here, we present an easily replicable procedure to identify said stable exposure domains, where image noise does not substantially add to textural feature values. Only by imaging at predetermined feature-invariant exposure levels and by adjusting exposure to expected activity concentrations, can textural features have a quantitative use in PET/CT. The necessary exposure levels are attainable by modern PET/CT systems in clinical routine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229560PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075630PMC
June 2020

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D receptor agonist radioligand study.

Transl Psychiatry 2020 01 8;10(1). Epub 2020 Jan 8.

Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D receptor agonist radioligand [C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.
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http://dx.doi.org/10.1038/s41398-019-0681-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026156PMC
January 2020

Improved Risk Stratification for Progression from Mild Cognitive Impairment to Alzheimer's Disease with a Multi-Analytical Evaluation of Amyloid-β Positron Emission Tomography.

J Alzheimers Dis 2020 ;74(1):101-112

Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.

Background: Amyloid-β (Aβ) accumulation in brain of patients with suspected Alzheimer's disease (AD) can be assessed by positron emission tomography (PET) in vivo. While visual classification prevails in the clinical routine, semiquantitative PET analyses may enable more reliable evaluation of cases with a visually uncertain, borderline Aβ accumulation.

Objective: We evaluated different analysis approaches (visual/semiquantitative) to find the most accurate and sensitive interpretation of Aβ-PET for predicting risk of progression from mild cognitive impairment (MCI) to AD.

Methods: Based on standard uptake value (SUV) ratios of a cortical-composite volume of interest of 18F-AV45-PET from MCI subjects (n = 396, ADNI database), we compared three different reference region (cerebellar grey matter, CBL; brainstem, BST; white matter, WM) normalizations and the visual read by receiver operator characteristics for calculating a hazard ratio (HR) for progression to Alzheimer's disease dementia (ADD).

Results: During a mean follow-up time of 45.6±13.0 months, 28% of the MCI cases (110/396) converted to ADD. Among the tested methods, the WM reference showed best discriminatory power and progression-risk stratification (HRWM of 4.4 [2.6-7.6]), but the combined results of the visual and semiquantitative analysis with all three reference regions showed an even higher discriminatory power.

Conclusion: A multi-analytical composite of visual and semiquantitative reference tissue analyses of 18F-AV45-PET gave improved risk stratification for progression from MCI to ADD relative to performance of single read-outs. This optimized approach is of special interest for prospective treatment trials, which demand a high accuracy.
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http://dx.doi.org/10.3233/JAD-190818DOI Listing
May 2021

A 3D Deep Residual Convolutional Neural Network for Differential Diagnosis of Parkinsonian Syndromes on F-FDG PET Images.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:3531-3534

Idiopathic Parkinsons disease and atypical parkinsonian syndromes have similar symptoms at early disease stages, which makes the early differential diagnosis difficult. Positron emission tomography with F-FDG shows the ability to assess early neuronal dysfunction of neurodegenerative diseases and is well established for clinical use. In the past decades, machine learning methods have been widely used for the differential diagnosis of parkinsonism based on metabolic patterns. Unlike these conventional machine learning methods relying on hand-crafted features, the deep convolutional neural networks, which have achieved significant success in medical applications recently, have the advantage of learning salient feature representations automatically and effectively. This advantage may offer more appropriate invisible features extracted from data for the enhancement of the diagnosis accuracy. Therefore, this paper develops a 3D deep convolutional neural network on F-FDG PET images for the automated early diagnosis. Furthermore, we depicted in saliency maps the decision mechanism of the deep learning method to assist the physiological interpretation of deep learning performance. The proposed method was evaluated on a dataset with 920 patients. In addition to improving the accuracy in the differential diagnosis of parkinsonism compared to state-of-the-art approaches, the deep learning methods also discovered saliency features in a number of critical regions (e.g., midbrain), which are widely accepted as characteristic pathological regions for movement disorders but were ignored in the conventional analysis of FDG PET images.
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http://dx.doi.org/10.1109/EMBC.2019.8856747DOI Listing
July 2019

Metabolic Correlates of Dopaminergic Loss in Dementia with Lewy Bodies.

Mov Disord 2020 04 16;35(4):595-605. Epub 2019 Dec 16.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Background: Striatal dopamine deficiency and metabolic changes are well-known phenomena in dementia with Lewy bodies and can be quantified in vivo by I-Ioflupane brain single-photon emission computed tomography of dopamine transporter and F-fluorodesoxyglucose PET. However, the linkage between both biomarkers is ill-understood.

Objective: We used the hitherto largest study cohort of combined imaging from the European consortium to elucidate the role of both biomarkers in the pathophysiological course of dementia with Lewy bodies.

Methods: We compared striatal dopamine deficiency and glucose metabolism of 84 dementia with Lewy body patients and comparable healthy controls. After normalization of data, we tested their correlation by region-of-interest-based and voxel-based methods, controlled for study center, age, sex, education, and current cognitive impairment. Metabolic connectivity was analyzed by inter-region coefficients stratified by dopamine deficiency and compared to healthy controls.

Results: There was an inverse relationship between striatal dopamine availability and relative glucose hypermetabolism, pronounced in the basal ganglia and in limbic regions. With increasing dopamine deficiency, metabolic connectivity showed strong deteriorations in distinct brain regions implicated in disease symptoms, with greatest disruptions in the basal ganglia and limbic system, coincident with the pattern of relative hypermetabolism.

Conclusions: Relative glucose hypermetabolism and disturbed metabolic connectivity of limbic and basal ganglia circuits are metabolic correlates of dopamine deficiency in dementia with Lewy bodies. Identification of specific metabolic network alterations in patients with early dopamine deficiency may serve as an additional supporting biomarker for timely diagnosis of dementia with Lewy bodies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27945DOI Listing
April 2020

A Survey of Molecular Imaging of Opioid Receptors.

Molecules 2019 Nov 19;24(22). Epub 2019 Nov 19.

Department of Nuclear Medicine, University of Bern, Inselspital, Freiburgstraße 18, 3010 Bern, Switzerland.

The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as μ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although -[methyl-C]morphine, -codeine and -heroin did not show significant binding . [C]Diprenorphine ([C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the μ-preferring agonist [C]carfentanil ([C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [C]DPN or [C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate μ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of μORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [C]GR103545 is validated for studies of κORs. Structures such as [C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.
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http://dx.doi.org/10.3390/molecules24224190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891617PMC
November 2019

Language in Mild Depression: How It Is Spoken, What It Is About, and Why It Is Important to Listen.

Psychiatr Danub 2019 Sep;31(Suppl 3):427-433

Department of Psychiatry, Narcology, Psychotherapy and Clinical Psychology, Samara State Medical University, 119-29, Krasnoarmeyskaya Street, 443030 Samara, Russia,

Background: Our previous research demonstrated that mild depression (MD) is characterized by patterns of atypical language use such as inverted word order, greater repetition, increased use of reflexive/personal (e.g. myself) or negative/ indefinite (e.g. nobody) pronouns, verbs in past tense, and other lexico-grammatical, stylistic and syntactic indicators (how the patient speaks). We now investigate the role of semantic features (what the patient speaks about) in diagnosing (why it is important to listen) affective states.

Subjects And Methods: 201 written narratives from 124 patients with MD and 77 healthy controls (HC), including 35 cases of normal sadness (NS), were studied using principle component lexis analysis. Statistical data evaluation was performed with SPSS-25 (p<0.05, significant) and included the Cohen's kappa for inter-rater reliability, nonparametric methods to measure between-group differences (Mann-Whitney U-test, Pearson Chi-square test, Kruskal-Wallis, one-way ANOVA), and discriminant analysis for modeling of semantic variables related to affective diagnostic types.

Results: Component lexis analysis revealed an exaggerated usage of semantic categories describing existential and family values in the texts of MD patients compared to HC. However, there were fewer cognitive and altruistic categories presented in patients' self-reports. The most substantial between-group difference was the lesser semantics of self-realization in MD patients, as well as their significantly lower ranking of social status' priorities. Communicative and hedonic values in MD speech displaced and predominated in ranking over the values of social status, versus the opposite relationship in HC speech. The discriminant model revealed a set of semantic indicators significantly distinguishing the MD, HC and NS groups (96.3%; Wilks' λ=0.001, p<0.001, r=0.996).

Conclusions: Linguistic structure and content of patients' verbalizations may serve as diagnostic markers of MD. Evaluation of psychosocial themes within the content of narratives should enable a better understanding of MD pathogenesis and emphasize the importance of monitoring social difficulties during treatment.
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September 2019

Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau.

Alzheimers Res Ther 2019 08 1;11(1):67. Epub 2019 Aug 1.

Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.

Background: Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer's disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal F-fluorodeoxyglucose positron emission tomography (FDG-PET) study.

Methods: Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings.

Results: Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex - 53%, p < 0.001; hippocampus - 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001).

Conclusion: Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.
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http://dx.doi.org/10.1186/s13195-019-0522-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670231PMC
August 2019

Management of Glucose Control in Noncritically Ill, Hospitalized Patients Receiving Parenteral and/or Enteral Nutrition: A Systematic Review.

J Clin Med 2019 Jun 28;8(7). Epub 2019 Jun 28.

Department of Diabetes, Endocrinology, Clinical Nutrition, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.

Hyperglycemia is a common occurrence in hospitalized patients receiving parenteral and/or enteral nutrition. Although there are several approaches to manage hyperglycemia, there is no consensus on the best practice. We systematically searched PubMed, Embase, Cochrane Central, and ClinicalTrials.gov to identify records (published or registered between April 1999 and April 2019) investigating strategies to manage glucose control in adults receiving parenteral and/or enteral nutrition whilst hospitalized in noncritical care units. A total of 15 completed studies comprising 1170 patients were identified, of which 11 were clinical trials and four observational studies. Diabetes management strategies entailed adaptations of nutritional regimens in four studies, while the remainder assessed different insulin regimens and administration routes. Diabetes-specific nutritional regimens that reduced glycemic excursions, as well as algorithm-driven insulin delivery approaches that allowed for flexible glucose-responsive insulin dosing, were both effective in improving glycemic control. However, the assessed studies were, in general, of limited quality, and we see a clear need for future rigorous studies to establish standards of care for patients with hyperglycemia receiving nutrition support.
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http://dx.doi.org/10.3390/jcm8070935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678336PMC
June 2019

Relationship of self-transcendence traits with in vivo dopamine D2/3 receptor availability and functional connectivity: An [ F]fallypride PET and fMRI study.

Synapse 2019 11 11;73(11):e22121. Epub 2019 Jul 11.

Neuroscience Research Institute, Gachon University, Incheon, South Korea.

Genetic research has implicated dopamine neurotransmission in the expression of the self-transcendence trait in humans. However, molecular imaging of dopaminergic markers is undocumented in relation to this personality trait. In this multimodal imaging study, we first investigated the relationship between the self-transcendence trait and in vivo dopamine D receptor availability using [ F]fallypride positron emission tomography (PET). We next conducted seed-based functional connectivity analyses using resting-state functional magnetic resonance imaging (rs-fMRI) data with regions derived from the PET analysis as seeds to explore the functional significance of D receptor availability foci associated with the self-transcendence trait. Twenty-one healthy subjects underwent high-resolution PET with [ F]fallypride and a subset of 18 subjects also completed 3-Tesla rs-fMRI. The Temperament and Character Inventory was used to measure the self-transcendence trait. A voxel-based whole brain analysis revealed that the [ F]fallypride binding potential (BP ) within the cluster of the left insula was significantly positively correlated with self-transcendence trait scores. A region-of-interest analysis also showed a significant positive correlation between self-transcendence and [ F]fallypride BP in the left insula. The exploratory [ F]fallypride BP seed-based rs-fMRI analysis showed that the functional connectivity from the left insula seed to the prefrontal cortices (including the inferior frontal region) was negatively associated with self-transcendence trait scores. The results of the present study suggest that D receptor-mediated neurotransmission in the left insula may constitute a significant neurobiological factor in the self-transcendence trait. The negative associations between BP seed-based functional connectivity and self-transcendence trait scores may suggest reduced prefrontal control in this personality trait.
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http://dx.doi.org/10.1002/syn.22121DOI Listing
November 2019

Response to the letter concerning the publication: Amyloid pathology fingerprint differentiates post-traumatic stress disorder and traumatic brain injury. Mohamed AZ, et al. NeuroImage Clinical 2018 June 5;19:716-726.

Neuroimage Clin 2019 22;23:101867. Epub 2019 May 22.

Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address:

In August 2018, Weiner and colleagues raised a red flag concerning certain errors in the tables and figures of our article, "Amyloid pathology fingerprint differentiates post-traumatic stress disorder and traumatic brain injury. NeuroImage Clinical 2018 Jun 5;19:716-726". We have addressed this in detail in our published "Corrigendum to 'Amyloid pathology fingerprint differentiates post-traumatic stress disorder and traumatic brain injury' NeuroImage: Clinical. 19 (2018) 716-726". However, recently Prof. Weiner and colleagues have raised a new issue in indicating that they could not 'replicate our results, despite accurately emulating our methods. We have prepared this letter in response to their recent letter.
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http://dx.doi.org/10.1016/j.nicl.2019.101867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538944PMC
January 2020