Publications by authors named "Henryk Barthel"

147 Publications

Binding characteristics of [F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET.

J Cereb Blood Flow Metab 2021 May 27:271678X211018904. Epub 2021 May 27.

Center for Neuropathology and Prion Research, University Hospital of Munich, LMU Munich, Munich, Germany.

The novel tau-PET tracer [F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer's disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.
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http://dx.doi.org/10.1177/0271678X211018904DOI Listing
May 2021

Feasibility of short imaging protocols for [F]PI-2620 tau-PET in progressive supranuclear palsy.

Eur J Nucl Med Mol Imaging 2021 May 22. Epub 2021 May 22.

Department of Psychiatry, University Hospital Cologne, Cologne, Germany.

Purpose: Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [F]PI-2620 tau-PET imaging of PSP.

Methods: Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [F]PI-2620 PET was performed by a dynamic 60-min scan. Distribution volume ratios (DVRs) were calculated using full and truncated scan durations (0-60, 0-50, 0-40, 0-30, and 0-20 min p.i.). Standardized uptake value ratios (SUVrs) were obtained 20-40, 30-50, and 40-60 min p.i.. All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP-RS from HCs in predefined subcortical and cortical target regions (effect size, area under the curve (AUC), multi-region classifier).

Results: 0-50 and 0-40 DVR showed equivalent effect sizes as 0-60 DVR (averaged Cohen's d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0-30 or 0-20 DVR. The 20-40 SUVr indicated the best performance of all static acquisition windows (averaged Cohen's d: 0.99). The globus pallidus internus discriminated patients with PSP-RS and HCs at a similarly high level for 0-60 DVR (AUC: 0.96), 0-40 DVR (AUC: 0.96), and 20-40 SUVr (AUC: 0.94). The multi-region classifier sensitivity of these time windows was consistently 86%.

Conclusion: Truncated and static imaging windows can be used for [F]PI-2620 PET imaging of PSP. 0-40 min dynamic scanning offers the best balance between accuracy and economic scanning.
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http://dx.doi.org/10.1007/s00259-021-05391-3DOI Listing
May 2021

Cortical [ F]PI-2620 Binding Differentiates Corticobasal Syndrome Subtypes.

Mov Disord 2021 May 5. Epub 2021 May 5.

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Background: Corticobasal syndrome is associated with cerebral protein aggregates composed of 4-repeat (~50% of cases) or mixed 3-repeat/4-repeat tau isoforms (~25% of cases) or nontauopathies (~25% of cases).

Objectives: The aim of this single-center study was to investigate the diagnostic value of the tau PET-ligand [ F]PI-2620 in patients with corticobasal syndrome.

Methods: Forty-five patients (71.5 ± 7.6 years) with corticobasal syndrome and 14 age-matched healthy controls underwent [ F]PI-2620-PET. Beta-amyloid status was determined by cerebral β-amyloid PET and/or CSF analysis. Subcortical and cortical [ F]PI-2620 binding was quantitatively and visually compared between β-amyloid-positive and -negative patients and controls. Regional [ F]PI-2620 binding was correlated with clinical and demographic data.

Results: Twenty-four percent (11 of 45) were β-amyloid-positive. Significantly elevated [ F]PI-2620 distribution volume ratios were observed in both β-amyloid-positive and β-amyloid-negative patients versus controls in the dorsolateral prefrontal cortex and basal ganglia. Cortical [ F]PI-2620 PET positivity was distinctly higher in β-amyloid-positive compared with β-amyloid-negative patients with pronounced involvement of the dorsolateral prefrontal cortex. Semiquantitative analysis of [ F]PI-2620 PET revealed a sensitivity of 91% for β-amyloid-positive and of 65% for β-amyloid-negative cases, which is in excellent agreement with prior clinicopathological data. Regardless of β-amyloid status, hemispheric lateralization of [ F]PI-2620 signal reflected contralateral predominance of clinical disease severity.

Conclusions: Our data indicate a value of [ F]PI-2620 for evaluating corticobasal syndrome, providing quantitatively and regionally distinct signals in β-amyloid-positive as well as β-amyloid-negative corticobasal syndrome. In corticobasal syndrome, [ F]PI-2620 may potentially serve for a differential diagnosis and for monitoring disease progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28624DOI Listing
May 2021

Finding our way through the labyrinth of dementia biomarkers.

Eur J Nucl Med Mol Imaging 2021 Apr 20. Epub 2021 Apr 20.

Department of Nuclear Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.1007/s00259-021-05301-7DOI Listing
April 2021

PET/MRI Delivers Multimodal Brain Signature in Alzheimer's Disease with De Novo PSEN1 Mutation.

Curr Alzheimer Res 2021 ;18(2):178-184

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

Background: Little is known so far about the brain phenotype and the spatial interplay of different Alzheimer's disease (AD) biomarkers with structural and functional brain connectivity in the early phase of autosomal-dominant AD (ADAD). Multimodal PET/MRI might be suitable to fill this gap.

Material And Methods: We presented a 31-year-old male patient without a family history of dementia with progressive worsening of memory and motor function. Two separate sessions of 3T PET/MRI acquisitions were arranged with the ß-amyloid tracer [F]Florbetaben and the secondgeneration tau tracer [F]PI-2620. Simultaneously acquired MRI consisted of high-resolution 3D T1, diffusion-tensor imaging (DTI), and resting-state fMRI. PET/MRI data were compared with ten age-matched healthy controls.

Results: Widespread β-amyloid depositions were found in cortical regions, and striatum (Thal stage III) along with tau pathology restricted to the mesial-temporal structures (Braak stage III/IV). Volumetric/shape analysis of subcortical structures revealed atrophy of the hippocampal-amygdala complex. In addition, cortical thinning was detected in the right middle temporal pole. Alterations of multiple DTI indices were noted in the major white matter fiber bundles, together with disruption of default mode and sensory-motor network functional connectivity. Molecular genetic analysis by next-generation sequencing revealed a heterozygote missense pathogenic variant of the PSEN1 (Met233Val).

Conclusion: Multimodal PET/MR imaging is able to deliver, in a one-stop-shop approach, an array of molecular, structural and functional brain information in AD due to de novo pathogenic variant, which can be studied for spatial interplay and might provide a rationale for initiating anti- amyloid/tau therapeutic approaches.
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http://dx.doi.org/10.2174/1567205018666210414111536DOI Listing
January 2021

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

Neurobiol Aging 2021 Jul 28;103:147.e1-147.e5. 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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.021DOI Listing
July 2021

Early detection of amyloid load using F-florbetaben PET.

Alzheimers Res Ther 2021 03 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).
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http://dx.doi.org/10.1186/s13195-021-00807-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005243PMC
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.
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http://dx.doi.org/10.2967/jnumed.120.250290DOI Listing
March 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 Jul 16;48(7):2110-2120. 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.
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http://dx.doi.org/10.1007/s00259-020-05156-4DOI Listing
July 2021

Clinical Utility of β-Amyloid PET Imaging in People Living With HIV With Cognitive Symptoms.

J Acquir Immune Defic Syndr 2021 06;87(2):826-833

Department of Nuclear Medicine, Brighton and Sussex University Hospitals, United Kingdom.

Background: Imaging with β-amyloid (Aβ) positron emission tomography (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 cerebrospinal fluid Aβ42, tau, and HIV RNA were obtained. FBB PET images were assessed visually by 3 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 was compared with SUVR of PLWH.

Results: Most participants were men (90%) of white ethnicity (90%) with a median age (interquartile range) of 59 (43-79) years. Median CD4 count was 682 (74-1056). All patients were on combination antiretroviral therapy with plasma and cerebrospinal fluid HIV RNA <40 copies/mL. Fourteen patients had objective cognitive impairment including 2 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.
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http://dx.doi.org/10.1097/QAI.0000000000002648DOI Listing
June 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.
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http://dx.doi.org/10.23736/S1824-4785.20.03293-8DOI Listing
March 2021

Switching on Brain PET to Light Up Amyloid Pathology In Vivo.

Authors:
Henryk Barthel

J Nucl Med 2020 12;61(Suppl 2):227S-228S

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

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http://dx.doi.org/10.2967/jnumed.120.251900DOI Listing
December 2020

Increased Immunosignals of Collagen IV and Fibronectin Indicate Ischemic Consequences for the Neurovascular Matrix Adhesion Zone in Various Animal Models and Human Stroke Tissue.

Front Physiol 2020 26;11:575598. Epub 2020 Oct 26.

Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.

Ischemic stroke causes cellular alterations in the "neurovascular unit" (NVU) comprising neurons, glia, and the vasculature, and affects the blood-brain barrier (BBB) with adjacent extracellular matrix (ECM). Limited data are available for the zone between the NVU and ECM that has not yet considered for neuroprotective approaches. This study describes ischemia-induced alterations for two main components of the neurovascular matrix adhesion zone (NMZ), i.e., collagen IV as basement membrane constituent and fibronectin as crucial part of the ECM, in conjunction with traditional NVU elements. For spatio-temporal characterization of these structures, multiple immunofluorescence labeling was applied to tissues affected by focal cerebral ischemia using a filament-based model in mice (4, 24, and 72 h of ischemia), a thromboembolic model in rats (24 h of ischemia), a coagulation-based model in sheep (2 weeks of ischemia), and human autoptic stroke tissue (3 weeks of ischemia). An increased fibronectin immunofluorescence signal demarcated ischemia-affected areas in mice, along with an increased collagen IV signal and BBB impairment indicated by serum albumin extravasation. Quantifications revealed a region-specific pattern with highest collagen IV and fibronectin intensities in most severely affected neocortical areas, followed by a gradual decline toward the border zone and non-affected regions. Comparing 4 and 24 h of ischemia, the subcortical fibronectin signal increased significantly over time, whereas neocortical areas displayed only a gradual increase. Qualitative analyses confirmed increased fibronectin and collagen IV signals in ischemic areas from all tissues and time points investigated. While the increased collagen IV signal was restricted to vessels, fibronectin appeared diffusely arranged in the parenchyma with focal accumulations associated to the vasculature. Integrin α appeared enriched in the vicinity of fibronectin and vascular elements, while most of the non-vascular NVU elements showed complementary staining patterns referring to fibronectin. This spatio-temporal characterization of ischemia-related alterations of collagen IV and fibronectin in various stroke models and human autoptic tissue shows that ischemic consequences are not limited to traditional NVU components and the ECM, but also involve the NMZ. Future research should explore more components and the pathophysiological properties of the NMZ as a possible target for novel neuroprotective approaches.
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http://dx.doi.org/10.3389/fphys.2020.575598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649770PMC
October 2020

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

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

Center for Neuropathology and Prion Research, University Hospital of Munich, LMU Munich, Munich, 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.
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http://dx.doi.org/10.1001/jamaneurol.2020.2526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341407PMC
November 2020

Amyloid-PET and F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias.

Lancet Neurol 2020 11;19(11):951-962

Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at University College London, London, UK.

Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and F-fluorodeoxyglucose (F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.
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http://dx.doi.org/10.1016/S1474-4422(20)30314-8DOI Listing
November 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.
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http://dx.doi.org/10.1002/hbm.25244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814756PMC
February 2021

First Tau PET Tracer Approved: Toward Accurate In Vivo Diagnosis of Alzheimer Disease.

Authors:
Henryk Barthel

J Nucl Med 2020 10;61(10):1409-1410

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

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http://dx.doi.org/10.2967/jnumed.120.252411DOI Listing
October 2020

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 04 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.
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http://dx.doi.org/10.1007/s00259-020-05030-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041674PMC
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 03 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.
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http://dx.doi.org/10.1007/s00259-020-05029-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036219PMC
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.
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http://dx.doi.org/10.1016/j.ejrad.2020.109243DOI Listing
October 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.
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http://dx.doi.org/10.1159/000506765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383156PMC
June 2020

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

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.

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

EANM practice guideline/SNMMI procedure standard for dopaminergic imaging in Parkinsonian syndromes 1.0.

Eur J Nucl Med Mol Imaging 2020 07 9;47(8):1885-1912. Epub 2020 May 9.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Purpose: This joint practice guideline or procedure standard was developed collaboratively by the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). The goal of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian syndromes.

Methods: Currently nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses. To date both EANM and SNMMI have published procedural guidelines for dopamine transporter imaging with single photon emission computed tomography (SPECT) (in 2009 and 2011, respectively). An EANM guideline for D2 SPECT imaging is also available (2009). Since the publication of these previous guidelines, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of dopamine transporter imaging with SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, [F]fluorodopa PET is now used in some centers for the differential diagnosis of parkinsonism, although procedural guidelines aiming to define standard procedures for [F]fluorodopa imaging in this setting are still lacking.

Conclusion: All these emerging issues are addressed in the present procedural guidelines for dopaminergic imaging in parkinsonian syndromes.
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http://dx.doi.org/10.1007/s00259-020-04817-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300075PMC
July 2020

Hypothesis and Theory: A Pathophysiological Concept of Stroke-Induced Acute Phase Response and Increased Intestinal Permeability Leading to Secondary Brain Damage.

Front Neurosci 2020 21;14:272. Epub 2020 Apr 21.

Clinic and Policlinic for Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Gut integrity impairment leading to increased intestinal permeability (IP) is hypothesized to be a trigger of critically illness. Approximately 15-20% of human ischemic stroke (IS) victims require intensive care, including patients with impaired level of consciousness or a high risk for developing life-threatening cerebral edema. Local and systemic inflammatory reactions are a major component of the IS pathophysiology and can significantly aggravate brain tissue damage. Intracerebral inflammatory processes following IS have been well studied. Until now, less is known about systemic inflammatory responses and IS consequences apart from a frequently observed post-IS immunosuppression. Here, we provide a hypothesis of a crosstalk between systemic acute phase response (APR), IP and potential secondary brain damage during acute and subacute IS stages supported by preliminary experimental data. Alterations of the acute phase proteins (APPs) C-reactive protein and lipopolysaccharide-binding protein and serum level changes of antibodies directed against -cell extract antigen (IgA-, IgM-, and IgG-anti-) were investigated at 1, 2, and 7 days following IS in ten male sheep. We found an increase of both APPs as well as a decrease of all anti- antibodies within 48 h following IS. This may indicate an early systemic APR and increased IP, and underlines the importance of the increasingly recognized gut-brain axis and of intestinal antigen release for systemic immune responses in acute and subacute stroke stages.
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http://dx.doi.org/10.3389/fnins.2020.00272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186394PMC
April 2020

Reshaping the Amyloid Buildup Curve in Alzheimer Disease? Partial-Volume Effect Correction of Longitudinal Amyloid PET Data.

J Nucl Med 2020 12 1;61(12):1820-1824. Epub 2020 May 1.

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

It was hypothesized that the brain β-amyloid buildup curve plateaus at an early symptomatic stage of Alzheimer disease (AD). Atrophy-related partial-volume effects (PVEs) degrade signal in hot-spot imaging techniques such as amyloid PET. The current study, a longitudinal analysis of amyloid-sensitive PET data, investigated the effect on the shape of the β-amyloid curve in AD when PVE correction (PVEC) is applied. We analyzed baseline and 2-y follow-up data for 216 symptomatic individuals on the AD continuum (positive amyloid status) enrolled in the Alzheimer's Disease Neuroimaging Initiative (17 with AD dementia and 199 with mild cognitive impairment), including F-florbetapir PET, MRI, and Mini Mental State Examination scores. For PVEC, the modified Müller-Gärtner method was performed. Compared with non-PVE-corrected data, PVE-corrected data yielded significantly higher changes in regional and composite SUV ratio (SUVR) over time ( = 0.0002 for composite SUVRs). Longitudinal SUVR changes in relation to Mini Mental State Examination decreases showed a significantly higher slope for the regression line in the PVE-corrected than in the non-PVE-corrected PET data ( = 7.1, = 0.008). These PVEC results indicate that the β-amyloid buildup curve does not plateau at an early symptomatic disease stage. A further evaluation of the impact of PVEC on the in vivo characterization of time-dependent AD pathology, including the reliable assessment and comparison of other amyloid tracers, is warranted.
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http://dx.doi.org/10.2967/jnumed.119.238477DOI Listing
December 2020