Publications by authors named "Osama Sabri"

235 Publications

Cognitive fatigue in multiple sclerosis is associated with alterations in the functional connectivity of monoamine circuits.

Brain Commun 2021 5;3(2):fcab023. Epub 2021 Mar 5.

Department of Neuroscience, Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9RR, UK.

Fatigue is a highly prevalent and debilitating symptom in multiple sclerosis, but currently the available treatment options have limited efficacy. The development of innovative and efficacious targeted treatments for fatigue in multiple sclerosis has been marred by the limited knowledge of the underlying mechanisms. One of the hypotheses postulates that multiple sclerosis pathology might cause reduced monoaminergic release in the central nervous system with consequences on motivation, mood and attention. Here, we applied the recently developed Receptor-Enriched Analysis of Functional Connectivity by Targets method to investigate whether patients with high and low fatigue differ in the functional connectivity (FC) of the monoamine circuits in the brain. We recruited 55 patients with multiple sclerosis, which were then classified as highly fatigued or mildly fatigued based on their scores on the cognitive sub-scale of the Modified Fatigue Impact scale. We acquired resting-state functional MRI scans and derived individual maps of connectivity associated with the distribution of the dopamine, noradrenaline and serotonin transporters as measured by positron emission tomography. We found that patients with high fatigue present decreased noradrenaline transporter (NAT)-enriched connectivity in several frontal and prefrontal areas when compared to those with lower fatigue. The NAT-enriched FC predicted negatively individual cognitive fatigue scores. Our findings support the idea that alterations in the catecholaminergic functional circuits underlie fatigue in multiple sclerosis and identify the NAT as a putative therapeutic target directed to pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023545PMC
March 2021

Low-degree trisomy 21 mosaicism promotes early-onset Alzheimer disease.

Neurobiol Aging 2021 Feb 28. Epub 2021 Feb 28.

Department of Neurology, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany. Electronic address:

Trisomy-21 mosaicism (mT21) with subclinical intellectual development disorder or physical phenotype has very rarely been associated with early-onset cognitive decline. Notably, early-onset Alzheimer's disease (EOAD) patients' family histories frequently suggest genetic causes other than autosomal-dominant APP/PSEN-1/2 mutations. We present an EOAD patient in his late fifties newly diagnosed with low-degree mT21 (13%/21% blood lymphocytes/ectodermal cells). We applied fluorescence in-situ hybridization to confirm a diagnosis of mT21. Multimodal positron-emission-tomography applying F-fluodesoxyglucose (metabolism), F-florbetaben (amyloid-β deposits) and F-PI-2620 (tau-deposits) tracers was used to confirm a diagnosis of EOAD according to the ATN-criteria of AD. Initial PET-studies revealed marked cerebral amyloid-β- and tau-pathology and parietotemporal hypometabolism, confirming EOAD according to the ATN-criteria of AD. A marked cognitive decline was accompanied by an increase in tau pathology in follow-up studies. This is the first case demonstrating that a low-degree APP gene-dose increase suffices to cause EOAD with prominent amyloid-β/tau pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.021DOI Listing
February 2021

Early detection of amyloid load using F-florbetaben PET.

Alzheimers Res Ther 2021 Mar 27;13(1):67. Epub 2021 Mar 27.

Fundació ACE Institut Català de Neurociències Aplicades, Research Center and Memory Unit - Universitat Internacional de Catalunya (UIC), Barcelona, Spain.

Background: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using F-florbetaben PET. Quantitative thresholds for the early (SUVR) and established (SUVR) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition.

Methods: The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition ("gray zone"), and subjects with established Aβ pathology.

Results: SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology.

Conclusions: This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention.

Trial Registration: Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-021-00807-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005243PMC
March 2021

Effective Valproic Acid Treatment in a Patient With Delusional Parasitosis Due to Corticobasal Syndrome and Alzheimer Disease.

J Clin Psychopharmacol 2021 Mar 12. Epub 2021 Mar 12.

Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, Augsburg, Germany Department of Nuclear Medicine, University Hospital, LMU Munich, Germany Department of Nuclear Medicine, University Hospital of Leipzig, Leipzig, Germany Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, Augsburg, Germany Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany German Center for Neurodegenerative Disorders (DZNE) Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JCP.0000000000001378DOI Listing
March 2021

Towards a Universal Readout for Fluorine-18 Labelled Amyloid Tracers: The CAPTAINs Study.

J Nucl Med 2021 Mar 12. Epub 2021 Mar 12.

University Hospital Cologne, Multimodal Neuroimaging Group, Department of Nuclear Medicine, Cologne & German Center of Neurodegenerative Disease (DZNE).

To date, three fluorine-18 labelled tracers have been approved for assessing cerebral amyloid plaques pathology to assist in the diagnosis of Alzheimer's Disease (AD). Although scanning protocols are relatively similar across tracers, FDA/EMA approved visual rating guidelines to render scans as positive or negative differ between the three tracers. The purpose of the present study was to assess the comparability of visual rating results when applying the three different FDA/EMA approved visual interpretation protocols to all three amyloid tracers both for experts and non-experts. In an international multicentre approach, both experts ( = 4) and non-experts ( = 3) rated scans acquired with fluorine-18 labelled florbetaben, florbetapir and flutemetamol. Scans obtained with each tracer were presented for reading according to all three approved visual rating protocols. In a randomized order, every single scan was rated by each reader according to all three protocols, resulting in a total of more than 700 image ratings. Raters were blinded for the amyloid tracer used and asked to rate each scan as positive or negative, giving a confidence judgement after each response. Percentage of visual reader agreement, inter-rater reliability and agreement of each visual read with binary quantitative measures of standard uptake value ratio based on a fixed threshold for positive and negative scans were computed. These metrics were analyzed separately for expert and non-expert groups. No significant differences in visual ratings across the different metrics of agreement were observed in the group of experts. Nominal differences suggested that the Florbetaben visual rating protocol achieved the highest interrater reliability and accuracy especially under low confidence conditions. For the group of non-experts significant differences in visual ratings were observed with overall moderate-to-fair accuracy and with the highest reliability for the Florbetapir visual rating procedure. We observed high interrater agreement despite applying different visual rating protocols for all fluorine-18 labelled amyloid tracers, suggesting sufficient potiential for a standardization for visual assessment of cerebral amyloid plaques. Non-experts, however, may need extensive training on reading fluorine-18 labelled amyloid scans and may particularly benefit from a universal readout to ensure comparability across visual evaluation strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.120.250290DOI Listing
March 2021

Striatal dopamine transporter availability and individual clinical course within the 1-year follow-up of deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

J Neurosurg 2021 Feb 19:1-7. Epub 2021 Feb 19.

2Neurosurgery, and.

Objective: Degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum is responsible for the motor symptoms in Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established procedure to alleviate these symptoms in advanced PD. Yet the mechanism of action, especially the effects of STN-DBS on the availability of striatal dopamine transporter (DAT) as a marker of nigrostriatal nerve cell function, remains largely unknown. The aim of this study was therefore to evaluate whether 1) DAT availability changes within 1 year of STN-DBS and 2) the clinical outcome can be predicted based on preoperative DAT availability.

Methods: Twenty-seven PD patients (mean age 62.7 ± 8.9 years; mean duration of illness 13.0 ± 4.9 years; PD subtypes: akinetic-rigid, n = 11; equivalence, n = 13; and tremor-dominant, n = 3) underwent [123I]FP-CIT SPECT preoperatively and after 1 year of STN-DBS. DAT availability as determined by the specific binding ratio (SBR) was assessed by volume of interest (VOI) analysis of the caudate nucleus and the putamen ipsilateral and contralateral to the clinically more affected side.

Results: Unified Parkinson's Disease Rating Scale (UPDRS) III scores improved significantly (mean preoperative on medication 25.6 ± 12.3, preoperative off medication 42.3 ± 15.2, postoperative on medication/off stimulation 41.4 ± 13.2, and postoperative on medication/on stimulation 16.1 ± 9.4; preoperative on medication vs postoperative on medication/on stimulation, p = 0.006), while the levodopa-equivalent daily dose was reduced (mean preoperative 957 ± 440 mg vs postoperative 313 ± 189 mg, p < 0.001). The SBR did not differ significantly before and 1 year after DBS, regardless of PD subtype. Preoperative DAT availability was not related to the change in UPDRS III score, but the change in DAT availability was significantly correlated with the change in UPDRS III score (contralateral head of the caudate VOI, p = 0.014; contralateral putamen VOI, p = 0.018).

Conclusions: Overall, DAT availability did not change significantly after 1 year of STN-DBS. However, on an individual basis, the improvement in UPDRS III score was associated with an increase in DAT availability, whereas DAT availability before STN-DBS surgery did not predict the clinical outcome. Whether a subtype-specific pattern of preoperative DAT availability can become a reliable predictor of successful STN-DBS must be evaluated in larger study cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2020.8.JNS192740DOI Listing
February 2021

Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

Eur J Nucl Med Mol Imaging 2021 Feb 16. Epub 2021 Feb 16.

Department of Nuclear Medicine, University Hospital Cologne, Cologne, Germany.

Purpose: In 2017, the Geneva Alzheimer's disease (AD) strategic biomarker roadmap initiative proposed a framework of the systematic validation AD biomarkers to harmonize and accelerate their development and implementation in clinical practice. Here, we use this framework to examine the translatability of the second-generation tau PET tracers into the clinical context.

Methods: All available literature was systematically searched based on a set of search terms that related independently to analytic validity (phases 1-2), clinical validity (phase 3-4), and clinical utility (phase 5). The progress on each of the phases was determined based on scientific criteria applied for each phase and coded as fully, partially, preliminary achieved or not achieved at all.

Results: The validation of the second-generation tau PET tracers has successfully passed the analytical phase 1 of the strategic biomarker roadmap. Assay definition studies showed evidence on the superiority over first-generation tau PET tracers in terms of off-target binding. Studies have partially achieved the primary aim of the analytical validity stage (phase 2), and preliminary evidence has been provided for the assessment of covariates on PET signal retention. Studies investigating of the clinical validity in phases 3, 4, and 5 are still underway.

Conclusion: The current literature provides overall preliminary evidence on the establishment of the second-generation tau PET tracers into the clinical context, thereby successfully addressing some methodological issues from the tau PET tracer of the first generation. Nevertheless, bigger cohort studies, longitudinal follow-up, and examination of diverse disease population are still needed to gauge their clinical validity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-05156-4DOI Listing
February 2021

CLINICAL UTILITY OF β-AMYLOID PET IMAGING IN PEOPLE LIVING WITH HIV WITH COGNITIVE SYMPTOMS.

J Acquir Immune Defic Syndr 2021 Feb 11. Epub 2021 Feb 11.

Centre for Global Health Research, Brighton and Sussex Med School, UK Department of Nuclear Medicine, Brighton and Sussex University Hospitals, UK Department of Nuclear Medicine, University of Leipzig, Germany Department of Infectious Diseases, University of Gothenburg, Sweden Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Sweden Department of Neuropsychology, Brighton and Sussex University Hospitals, UK Faculty of Health, University of Plymouth, UK.

Background: Imaging with β-amyloid (Aβ) PET has the potential to aid the diagnosis of the cause of cognitive impairment affecting people living with HIV (PLWH) when neurodegenerative disorders are considered. We evaluated the clinical utility of [18F]Florbetaben (FBB) in PLWH with cognitive symptoms.

Methods: Imaging with FBB PET was performed in 20 patients with cognitive concerns about dementia. Neuropsychological testing, plasma neurofilament light protein, plasma Aβ40, Aβ42 and CSF Aβ42, tau, and HIV RNA were obtained. FBB PET images were assessed visually by three readers blinded to the clinical diagnosis, and quantitatively by obtaining a composite cortical to cerebellar cortex standardized uptake value ratio (SUVR). FBB SUVR from 10 age-matched healthy controls were compared to SUVR of PLWH.

Results: Most participants were male (90%) of white ethnicity (90%) with a median age (IQR) of 59 (43-79) years. Median CD4 count was 682 (74-1056). All patients were on cART with plasma and CSF HIV RNA< 40 copies/mL. Fourteen patients had objective cognitive impairment including two who met clinical criteria for a diagnosis of dementia. No significant differences in composite SUVRs between PLWH and controls [mean (SD): 1.18 (0.03) vs 1.16 (0.09); p=0.37] were observed. Four patients were FBB+ with the highest SUVR in the posterior cingulate, superior temporal and frontal superior lobe. Amyloid PET results contributed to a change in diagnosis and treatment for 10 patients.

Conclusion: [18F]Florbetaben PET has potential as an adjunctive tool in the diagnosis of PLWH with cognitive impairment, increasing diagnostic certainty and optimizing management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002648DOI Listing
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22041645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915902PMC
February 2021

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

Pediatr Blood Cancer 2021 Apr 3;68(4):e28903. Epub 2021 Feb 3.

Department of Radiology, Medical Faculty of the Martin-Luther-University, Halle (Saale), Germany.

Background: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging.

Patients, Materials, And Methods: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment.

Results: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient.

Conclusions: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28903DOI Listing
April 2021

Improved in vivo PET imaging of the adenosine A receptor in the brain using [F]FLUDA, a deuterated radiotracer with high metabolic stability.

Eur J Nucl Med Mol Imaging 2021 Feb 2. Epub 2021 Feb 2.

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

Purpose: The adenosine A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A receptor radiotracer and report herein the preclinical evaluation of [F]FLUDA, a deuterated isotopologue of [F]FESCH.

Methods: [F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats.

Results: [F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72-180 GBq/μmol. Autoradiography proved A receptor-specific accumulation of [F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [F]FLUDA compared to that of [F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [F]FLUDA towards striatal A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [F]FLUDA.

Conclusions: The new radiotracer [F]FLUDA is suitable to detect the availability of the A receptor in the brain with high target specificity. It is regarded ready for human application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-05164-4DOI Listing
February 2021

Practical setting and potential applications of interventions guided by PET/MRI.

Q J Nucl Med Mol Imaging 2021 Mar 10;65(1):43-50. Epub 2020 Dec 10.

Innovation Center Computer Assisted Surgery, University of Leipzig, Leipzig, Germany.

Multimodality imaging has emerged from a vision thirty years ago to routine clinical use today. Positron emission tomography (PET)/magnetic resonance imaging (MRI) is still relatively new in this arena and particularly suitable for clinical research and technical development. PET/MRI-guidance for interventions opens up opportunities for novel treatments but at the same time demands certain technical and organizational requirements to be fulfilled. In this work, we aimed to demonstrate a practical setting and potential application of PET/MRI guidance of interventional procedures. The superior quantitative physiologic information of PET, the various unique imaging characteristics of MRI, and the reduced radiation exposure are the most relevant advantages of this technique. As a noninvasive interventional tool, focused ultrasound (FUS) ablation of tumor cells would benefit from PET/MRI for diagnostics, treatment planning and intervention. Yet, technical limitations might impeed preclinical research, given that PET/MRI sites are per se not designed as interventional suites. Nonetheless, several approaches have been offered in the past years to upgrade MRI suites for interventional purposes. Taking advantage of state of the art and easy-to-use technology it is possible to create a supporting infrastructure that is suitable for broad preclinical adaption. Several aspects are to be addressed, including remote control of the imaging system, display of the imaging results, communication technology, and implementation of additional devices such as a FUS platform and an MR-compatible robotic system for positioning of the FUS equipment. Feasibility could be demostrated with an examplary experimental setup for interventional PET/MRI. Most PET/MRI sites could allow for interventions with just a few add-ons and modifications, such as comunication, in room image display and sytems control. By unlocking this feature, and driving preclinical research in interventional PET/MRI, translation of the protocol and methodology into clinical settings seems feasible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23736/S1824-4785.20.03293-8DOI Listing
March 2021

Higher HbA1c levels associate with lower hippocampal serotonin transporter availability in non-diabetic adults with obesity.

Sci Rep 2020 12 7;10(1):21383. Epub 2020 Dec 7.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

The current study aimed to investigate whether the in vivo availability of central serotonin reuptake transporters (5-HTT) is associated with plasma levels of glycosylated hemoglobin (HbA1c) in non-diabetic humans with obesity. 5-HTT availability was measured by using positron emission tomography (PET) imaging with the 5-HTT selective radiotracer [C]DASB in 23 non-diabetic individuals with obesity and 14 healthy, non-obesity controls. Parametric images of binding potential BP were generated from the PET data and analyzed together with HbA1c levels by using volume of interest analysis for brain areas relevant to appetite control. Voxel-based morphometry (VBM) of individual magnetic resonance imaging data was further performed to correlate grey matter density (GMD) maps with HbA1c. We found significant negative correlations between HbA1c levels and BP in right and left hippocampus in obesity (r = - 0.717, p < 0.001, and r = - 0.557, p = 0.006, respectively). VBM analyses revealed that higher HbA1c levels were associated with GMD in the right para-hippocampal area. Our results indicate that chronically high blood glucose levels may evoke changes in hippocampal 5-HTT levels that are in part tied to local microstructure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-78227-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721891PMC
December 2020

Interim positron emission tomography in diffuse large B-cell lymphoma.

J Nucl Med 2020 Nov 27. Epub 2020 Nov 27.

Universitaet Leipzig, Institut fuer Medizinische Informatik, Statistik und Epidemiologie, Germany.

In diffuse large B-cell lymphoma, early assessment of treatment response by 18-fluorodeoxyglucose positron emission tomography (PET) may trigger treatment modification. Reliable identification of good and poor responders is important. We compared three competing methods of interim PET evaluation. Images from 449 patients participating in the 'Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas' trial were re-analyzed by applying the visual Deauville score and the standardized uptake value (SUV)-based qPET and ΔSUV scales to interim PET scans performed after two cycles of chemotherapy. qPET relates residual lymphoma 18-fluorodeoxyglucose uptake to physiological liver uptake, converting the ordinal Deauville scale into a continuous scale and permitting a direct comparison with the continuous ΔSUV scale, which is based on SUV changes between baseline and interim scans. Positive and negative predictive values were calculated for progression-free survival. Using established thresholds to distinguish between good and poor responders (visual Deauville score 1-3 vs. 4-5; ΔSUV >66% vs. ΔSUV ≤66%), the positive predictive value was significantly lower with Deauville than ΔSUV (38.4% versus 56.6%; = 0.03). qPET and ΔSUV were strongly correlated on the log scale (Pearson's r=0.75). When plotted along corresponding percentiles, the positive predictive value curves for qPET and ΔSUV were superimposable, with low values up to the 85th percentile and a steep rise thereafter. The recommended threshold of 66% SUV reduction for the identification of poor responders was equivalent to qPET=2.26 corresponding to score 5 on the visual Deauville scale. The negative predictive value curves were also superimposable, but remained flat between 80% and 70%. Continuous scales are better suited for interim PET-based outcome prediction than the ordinal Deauville scale. qPET and ΔSUV essentially carry the same information. The proportion of poor risk patients identified is less than 15%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.120.255034DOI Listing
November 2020

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

JAMA Neurol 2020 11;77(11):1408-1419

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.

Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP.

Design, Setting, And Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019.

Main Outcomes And Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex.

Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region.

Conclusions And Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2020.2526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341407PMC
November 2020

Loeffler's Endocarditis: An Integrated Multimodality Approach.

J Am Soc Echocardiogr 2020 12 29;33(12):1427-1441. Epub 2020 Oct 29.

Division of Cardiology, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.

Loeffler's endocarditis (LE) is the cardiac manifestation of hypereosinophilic syndrome, a rare systemic disease characterized by the sustained production of eosinophils leading to organ damage. Few data, principally by case reports, are available regarding the diagnostic workup in patients with suspected LE. Thus, we have performed a systematic search of the literature dealing with imaging in LE and propose an integrated multimodality imaging approach in the cardiac diagnostics of LE patients. The aim is to provide an updated state-of-the-art review focused on noninvasive and invasive imaging modalities for this rare and underdiagnosed disease. Standard and advanced echocardiography are typically the first cardiac imaging examinations when LE is suspected and they are also used later in follow-up for prognostic stratification and assessing response to treatment. Cardiac magnetic resonance provides a more detailed anatomical and functional evaluation of cardiac chambers, tissue characterization for the presence and extension of myocardial edema and fibrosis, and ventricular thrombi identification. Computed tomography scan and [18F]-fluoro-deoxy-glucose positron emission tomography may be helpful in selected cases to evaluate the cardiac involvement of LE as well as the other noncardiac manifestations of hypereosinophilic syndrome. Endomyocardial biopsy may be considered in patients with high clinical suspicion of LE if noninvasive imaging findings are confusing or not conclusive. The appropriate use of invasive and noninvasive imaging modalities, combining the available techniques with the patients' clinical features, will hopefully lead to early diagnosis, more accurate staging of disease, and timely treatment of LE that may prevent the irreversible myocardial damage of LE and adverse cardiovascular events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.echo.2020.09.002DOI Listing
December 2020

JuSpace: A tool for spatial correlation analyses of magnetic resonance imaging data with nuclear imaging derived neurotransmitter maps.

Hum Brain Mapp 2021 Feb 20;42(3):555-566. Epub 2020 Oct 20.

Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany.

Recent studies have shown that drug-induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (rsfMRI) are associated with the distribution of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a toolbox (JuSpace) allowing for cross-modal correlation of MRI-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma-aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinson's disease patients (PD) and risperidone-induced changes in rsfMRI and cerebral blood flow (CBF). Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD and dopaminergic (D2) and serotonergic systems (5-HT1b). Risperidone induced CBF alterations were correlated with its main targets in serotonergic and dopaminergic systems. JuSpace provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hbm.25244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814756PMC
February 2021

Effects of Hyperthyroidism on Adipose Tissue Activity and Distribution in Adults.

Thyroid 2021 03 18;31(3):519-527. Epub 2020 Nov 18.

Medical Department III-Endocrinology, Nephrology, Rheumatology; Leipzig, Germany.

Positron emission tomography (PET) has provided evidence that adult humans retain metabolically active brown adipose tissue (BAT) depots. Thyroid hormones (TH) stimulate BAT thermogenesis by central and peripheral mechanisms. However, the effect of hyperthyroidism on BAT activity and BAT volume in humans is yet not fully understood. The aim of this study was to investigate the effect of TH on (i) the metabolic activity of brown and white adipose tissue (WAT) depots, (ii) on abdominal visceral and subcutaneous adipose tissue area, and (iii) on serum levels of metabolically active cytokines. Nineteen patients with overt hyperthyroidism were investigated through repeated 2-[F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (2-[F]FDG PET/CT) in the hyperthyroid and in the euthyroid state. The 2-[F]FDG uptake was calculated as standard uptake ratio with blood pool as reference. Fat areas were quantified by means of CT segmentation. Serum levels of fetuin A and B, fibroblast growth factor 21, adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4, pro-enkephalin, pro-neurotensin, and neuregulin 4 were determined in the hyperthyroid and in the euthyroid state for each subject. 2-[F]FDG uptake was increased in the hyperthyroid state in BAT in comparison with the euthyroid phase ( = 0.001). There was no correlation between serum free triiodothyronine (fT3) and free thyroxine (fT4) levels and 2-[F]FDG uptake in BAT or WAT. In the hyperthyroid state, fT3 levels were positively associated with skeletal muscle standardized uptake value ratios. Areas of visceral adipose tissue and skeletal muscle were significantly decreased in hyperthyroidism. AFABP levels correlated positively with fT3 ( = 0.031, β = 0.28) and fT4 ( = 0.037, β = 0.27) in the hyperthyroid state. Our results suggest that the contribution of increased TH levels to the glucose uptake of BAT and WAT is low compared with that of the skeletal muscle. Hyperthyroid subjects have reduced areas of visceral adipose tissue and increased AFABP levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2019.0806DOI Listing
March 2021

Increased pulmonary serotonin transporter in patients with chronic obstructive pulmonary disease who developed pulmonary hypertension.

Eur J Nucl Med Mol Imaging 2021 Apr 3;48(4):1081-1092. Epub 2020 Oct 3.

Department of Respiratory Medicine, University Hospital Leipzig, Liebigstrasse 20, 04103, Leipzig, Germany.

Purpose: Pulmonary hypertension (PH) is characterized by a progressive remodelling of the pulmonary vasculature resulting in right heart failure and eventually death. The serotonin transporter (SERT) may be involved in the pathogenesis of PH in patients with chronic-obstructive pulmonary disease (COPD). This study investigated for the first time the SERT in vivo availability in the lungs of patients with COPD and PH (COPD+PH).

Methods: SERT availability was assessed using SERT-selective [C]DASB and positron emission tomography/computed tomography (PET/CT) with dynamic acquisition over 30 min in 4 groups of 5 participants each: COPD, COPD+PH, pulmonary arterial hypertension, and a healthy control (HC). Time activity curves were generated based on a volume of interest within the middle lobe. Tissue-to-blood concentration ratios after 25 to 30 min (TTBR) served as receptor parameter for group comparison and were corrected for lung tissue attenuation. Participants underwent comprehensive pulmonary workup. Statistical analysis included group comparisons and correlation analysis.

Results: [C]DASB uptake peak values did not differ among the cohorts after adjusting for lung tissue attenuation, suggesting equal radiotracer delivery. Both the COPD and COPD+PH cohort showed significantly lower TTBR values after correction for lung attenuation than HC. Attenuation corrected TTBR values were significantly higher in the COPD+PH cohort than those in the COPD cohort and higher in non-smokers than in smokers. They positively correlated with invasively measured severity of PH and inversely with airflow limitation and emphysema. Considering all COPD patients ± PH, they positively correlated with right heart strain (NT-proBNP).

Conclusion: By applying [C]DASB and PET/CT, semiquantitative measures of SERT availability are demonstrated in the lung vasculature of patients with COPD and/or PH. COPD patients who developed PH show increased pulmonary [C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-05056-7DOI Listing
April 2021

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [F] fluspidine and [F] fallypride PET study.

Eur J Nucl Med Mol Imaging 2021 Apr 29;48(4):1103-1115. Epub 2020 Sep 29.

Department of Nuclear Medicine, University of Leipzig Medical Center, Leipzig, Germany.

Purpose: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [F] fluspidine and [F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD.

Methods: Using [F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot.

Results: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%).

Conclusions: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-05030-3DOI Listing
April 2021

(+)-[F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand-results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer's disease and healthy controls.

Eur J Nucl Med Mol Imaging 2021 Mar 16;48(3):731-746. Epub 2020 Sep 16.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

Purposes: We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer's disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[F]Flubatine binding; and whether (+)-[F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated.

Methods: We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [C]PiB PET/MRI examination. (+)-[F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses.

Results: With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[F]Flubatine binding of approximately 15% but also standard deviation of 0.4-70%. Cognitive test data and (+)-[F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p < 0.05 each). In AD patients, (+)-[F]Flubatine binding and [C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[F]Flubatine binding and [C]PiB accumulation in the white matter was found. No adverse event related to (+)-[F]Flubatine occurred.

Conclusion: (+)-[F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR-targeting PET ligand in further clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-05029-wDOI Listing
March 2021

Quantitative susceptibility mapping in β-Amyloid PET-stratified patients with dementia and healthy controls - A hybrid PET/MRI study.

Eur J Radiol 2020 Oct 29;131:109243. Epub 2020 Aug 29.

Department of Nuclear Medicine, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany.

Purpose: Post-mortem and in-vivo MRI data suggest an accumulation of iron in the brain of Alzheimer's disease (AD) patients. The majority of studies in clinically diagnosed AD patients found an increase of iron-sensitive MRI signals in the putamen. As the clinical diagnosis shows only a moderate sensitivity, Aβ-PET was used to further stratify patients with the clinical diagnosis of AD. Aim of this exploratory study was to examine whether Aβ-positive (AD) and Aβ-negative (non-AD) patients differ in their regional magnetic susceptibility compared to healthy controls (HCs) and whether regional susceptibility values correlate with mini mental state examination (MMSE) scores or global Aβ-load.

Methods: We retrospectively analyzed [C]PiB PET/MRI data of 11 HCs, 16 AD and 10 non-AD patients. We used quantitative susceptibility mapping (QSM) as iron-sensitive MRI signal measured at the 3 T PET/MR scanner. Global cerebral Aβ-load was determined by composite [C]PiB SUV ratios.

Results: Compared to HCs, AD patients showed higher QSM values in putamen (0.049 ± 0.033 vs. 0.002 ± 0.031; p = 0.006), while non-AD patients showed lower QSM values in caudate nucleus (0.003 ± 0.027 vs. 0.051 ± 0.039; p = 0.006). There was a trend towards a significant correlation between putaminal QSM and MMSE values (ρ=-0.340, p = 0.053). In AD patients, global Aβ-load and putaminal QSM values were significantly correlated (ρ=-0.574, p = 0.020).

Conclusions: These data indicate that AD and non-AD patients may show different cerebral iron pathologies which might be detectable by QSM MRI, and might be linked to neurodegeneration. Overall, the data encourage further investigations in well-defined patient cohorts to clarify the value of QSM/magnetic susceptibility in the course of neurodegenerative diseases and its potential as diagnostic biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejrad.2020.109243DOI Listing
October 2020

Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients.

Sci Rep 2020 09 4;10(1):14651. Epub 2020 Sep 4.

Department of Neurology, University of Leipzig, Leipzig, Germany.

The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood, and exerts anti-inflammatory and neuroprotective effects. Alterations of monoamine signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. We assessed central noradrenaline transporter (NAT) availability using positron emission tomography (PET) and the NAT selective radiotracer S,S-[C]O-methylreboxetine in immunotherapy-naïve patients with relapsing-remitting MS (RRMS; n = 11) compared to healthy controls (HC; n = 12), and its association to lesion load, time since manifestation, the expanded disability status scale (EDSS), the fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and Beck Depression Inventory (BDI). We found NAT availability to be increased in the thalamus, amygdala, putamen and pons/midbrain of MS patients. No relation to clinical or psychometric variables was found. These first data indicate higher NAT availability in subcortical brain regions of immunotherapy-naïve RRMS patients. If these changes of noradrenergic neurotransmission predispose to psychiatric symptoms or associate with disease activity needs to be investigated in longitudinal studies or a larger sample which allows subgroup analyses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-70732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474089PMC
September 2020

Colocalization of Tau but Not β-Amyloid with Cortical Superficial Siderosis in a Case with Probable CAA.

Case Rep Neurol 2020 May-Aug;12(2):232-237. Epub 2020 Jun 29.

Institute for Stroke and Dementia Research, University Hospital of Munich, Ludwig-Maximilians-Universität (LMU), Munich, Germany.

Cortical superficial siderosis (cSS) is a common feature in patients with cerebral amyloid angiopathy (CAA). The correlation between β-amyloid and/or tau pathology and the occurrence of cSS is unclear. We report on an 80-year-old male patient who was diagnosed with probable CAA according to modified Boston criteria and underwent longitudinal magnetic resonance imaging, amyloid positron emission tomography (PET), and additional tau PET imaging. Amyloid deposition presented predominantly in the contralateral hemisphere not affected by cSS. In contrast, tau deposition was predominantly overlapping with brain regions affected by cSS. Amyloid deposition was not different in the vicinity of cSS whereas tau depositions were elevated in the vicinity of CSS-affected regions compared to non-cSS-affected brain regions. This case of probable CAA suggests that cSS may be associated with a locally elevated tau pathology but not with increased fibrillary amyloid deposition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000506765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383156PMC
June 2020

Comparison of Interim PET Response to Second-Line Versus First-Line Treatment in Classic Hodgkin Lymphoma: Contribution to the Development of Response Criteria for Relapsed or Progressive Disease.

J Nucl Med 2021 Mar 6;62(3):338-341. Epub 2020 Aug 6.

Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany.

In first-line treatment of Hodgkin lymphoma (HL), Deauville scores 1-3 define complete metabolic remission. Interim F-FDG PET is also used for relapse-treatment adaptation; however, PET response criteria are not validated for relapse treatment. We performed a pairwise comparative analysis of early response to first- and second-line treatments in 127 patients with classic HL who experienced relapse. The patients participated in the prospective, multicenter EuroNet-PHL-C1 study. Residual uptake was measured retrospectively using the qPET method, a validated semiautomatic quantitative extension of the Deauville score. Empiric cumulative distribution functions of the qPET values were used to systematically analyze the response to first- and second-line treatments. Individual patients responded variably to first- and second-line treatments. However, the empiric cumulative distribution functions of the qPET values from all patients were nearly superimposable. The findings support that first- and second-line treatments in HL do not require different response criteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.120.247924DOI Listing
March 2021

A realistic phantom of the human head for PET-MRI.

EJNMMI Phys 2020 Aug 5;7(1):52. Epub 2020 Aug 5.

Department of Nuclear Medicine, Leipzig University Hospital, Liebigstr. 18, Leipzig, Germany.

Background: The combination of positron emission tomography (PET) and magnetic resonance imaging (MRI) (PET-MRI) is a unique hybrid imaging modality mainly used in oncology and neurology. The MRI-based attenuation correction (MRAC) is crucial for correct quantification of PET data. A suitable phantom to validate quantitative results in PET-MRI is currently missing. In particular, the correction of attenuation due to bone is usually not verified by commonly available phantoms. The aim of this work was, thus, the development of such a phantom and to explore whether such a phantom might be used to validate MRACs.

Method: Various materials were investigated for their attenuation and MR properties. For the substitution of bone, water-saturated gypsum plaster was used. The attenuation of 511 keV annihilation photons was regulated by addition of iodine. Adipose tissue was imitated by silicone and brain tissue by agarose gel, respectively. The practicability with respect to the comparison of MRACs was checked as follows: A small flask inserted into the phantom and a large spherical phantom (serving as a reference with negligible error in MRAC) were filled with the very same activity concentration. The activity concentration was measured and compared using clinical protocols on PET-MRI and different built-in and offline MRACs. The same measurements were carried out using PET-CT for comparison.

Results: The phantom imitates the human head in sufficient detail. All tissue types including bone were detected as such so that the phantom-based comparison of the quantification accuracy of PET-MRI was possible. Quantitatively, the activity concentration in the brain, which was determined using different MRACs, showed a deviation of about 5% on average and a maximum deviation of 11% compared to the spherical phantom. For PET-CT, the deviation was 5%.

Conclusions: The comparatively small error in quantification indicates that it is possible to construct a brain PET-MRI phantom that leads to MR-based attenuation-corrected images with reasonable accuracy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40658-020-00320-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406590PMC
August 2020

Generalization of deep learning models for ultra-low-count amyloid PET/MRI using transfer learning.

Eur J Nucl Med Mol Imaging 2020 12 13;47(13):2998-3007. Epub 2020 Jun 13.

Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.

Purpose: We aimed to evaluate the performance of deep learning-based generalization of ultra-low-count amyloid PET/MRI enhancement when applied to studies acquired with different scanning hardware and protocols.

Methods: Eighty simultaneous [F]florbetaben PET/MRI studies were acquired, split equally between two sites (site 1: Signa PET/MRI, GE Healthcare, 39 participants, 67 ± 8 years, 23 females; site 2: mMR, Siemens Healthineers, 64 ± 11 years, 23 females) with different MRI protocols. Twenty minutes of list-mode PET data (90-110 min post-injection) were reconstructed as ground-truth. Ultra-low-count data obtained from undersampling by a factor of 100 (site 1) or the first minute of PET acquisition (site 2) were reconstructed for ultra-low-dose/ultra-short-time (1% dose and 5% time, respectively) PET images. A deep convolution neural network was pre-trained with site 1 data and either (A) directly applied or (B) trained further on site 2 data using transfer learning. Networks were also trained from scratch based on (C) site 2 data or (D) all data. Certified physicians determined amyloid uptake (+/-) status for accuracy and scored the image quality. The peak signal-to-noise ratio, structural similarity, and root-mean-squared error were calculated between images and their ground-truth counterparts. Mean regional standardized uptake value ratios (SUVR, reference region: cerebellar cortex) from 37 successful site 2 FreeSurfer segmentations were analyzed.

Results: All network-synthesized images had reduced noise than their ultra-low-count reconstructions. Quantitatively, image metrics improved the most using method B, where SUVRs had the least variability from the ground-truth and the highest effect size to differentiate between positive and negative images. Method A images had lower accuracy and image quality than other methods; images synthesized from methods B-D scored similarly or better than the ground-truth images.

Conclusions: Deep learning can successfully produce diagnostic amyloid PET images from short frame reconstructions. Data bias should be considered when applying pre-trained deep ultra-low-count amyloid PET/MRI networks for generalization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-04897-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680289PMC
December 2020

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits.

Neuropsychopharmacology 2020 08 30;45(9):1482-1489. Epub 2020 May 30.

Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton, UK.

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Our main analysis showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. In our exploratory analysis, we found that MPH-induced regional variations in the DAT and NET-enriched FC maps were significantly correlated with some of the inter-individual differences on key behavioural responses associated with the reinforcement-learning task. Our findings show that main MPH-related FC changes at rest can be understood through the distribution of DAT in the brain. Furthermore, they suggest that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to engagement of distinct molecular targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-020-0724-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360745PMC
August 2020

Clinical suspicion of spondylodiscitis with equivocal MRI findings: does diffusion-weighted imaging prove helpful here?

Acta Radiol 2021 Mar 29;62(3):394-400. Epub 2020 May 29.

Department for Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.

Background: Despite the high sensitivity of magnetic resonance imaging (MRI), early detection of spondylodiscitis (SpD) remains challenging due to its low specificity.

Purpose: To assess the diagnostic value of diffusion-weighted imaging (DWI) in suspected cases of SpD with ambiguous early MRI findings in the differentiation of degenerative disorders (DD).

Material And Methods: In this prospective study, 52 patients suspected of having SpD underwent a whole-spine 3-T MRI scan comprising sagittal DWI. Of 58 conspicuous, T2-weighted, signal increased discs, 39 were successfully evaluated using DWI. Apparent diffusion coefficient (ADC) values and ADC maps were blindly analyzed using the region of interest of the conspicuous disc and a normal adjacent reference disc. Intraindividual ratios (conspicuous disc: reference disc) were calculated.

Results: All conspicuous discs showed increased absolute ADC values, which did not differ significantly between SpD (n = 22) and DD (n = 17). However, ADC ratio was significantly higher in SpD vs. DD ( < 0.05). In receiver operating characteristic curve analysis, an ADC ratio threshold of 1.6 resulted in 45% sensitivity and 88% specificity (area under the curve = 0.69) for SpD diagnosis.

Conclusion: The absolute ADC value does not provide a reliable diagnosis of SpD. Increased diffusivity can be an indication of infection but should always be discussed in the context of existing disc degeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0284185120927905DOI Listing
March 2021

Exploiting the Full Potential of β-Amyloid and Tau PET Imaging for Drug Efficacy Testing.

J Nucl Med 2020 08 15;61(8):1105-1106. Epub 2020 May 15.

Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.119.228346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413238PMC
August 2020