Publications by authors named "Klaus Fliessbach"

84 Publications

Quantifying progression in primary progressive aphasia with structural neuroimaging.

Authors:
Jolina Lombardi Benjamin Mayer Elisa Semler Sarah Anderl-Straub Ingo Uttner Jan Kassubek Janine Diehl-Schmid Adrian Danek Johannes Levin Klaus Fassbender Klaus Fliessbach Anja Schneider Hans-Jürgen Huppertz Holger Jahn Alexander Volk Johannes Kornhuber Bernhard Landwehrmeyer Martin Lauer Johannes Prudlo Jens Wiltfang Matthias L Schroeter Albert Ludolph Markus Otto

Alzheimers Dement 2021 Mar 30. Epub 2021 Mar 30.

Department of Neurology, University Hospital Ulm, Ulm, Germany.

Introduction: The term primary progressive aphasia (PPA) sums up the non-fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression.

Methods: Structural brain imaging and an extensive assessment were applied at baseline and up to 4-year(s) follow-up in 269 participants. With automated atlas-based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials.

Results: At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (-17%) and of the left temporal lobe for svPPA (-34%) and lvPPA (-24%). Severest progression within 1-year follow-up occurred in the basal ganglia in nfvPPA (-7%), in the hippocampus/amygdala in svPPA (-9%), and in (medial) temporal regions in lvPPA (-6%).

Conclusion: PPA presents as a left-dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant-specific.
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http://dx.doi.org/10.1002/alz.12323DOI Listing
March 2021

Generation of a set of isogenic iPSC lines carrying all APOE genetic variants (Ɛ2/Ɛ3/Ɛ4) and knock-out for the study of APOE biology in health and disease.

Authors:
Benjamin Schmid Bjørn Holst Christian Clausen Lamiaa Bahnassawy Peter Reinhardt Margot H M Bakker Eva Díaz-Guerra Carlos Vicario Pamela V Martino-Adami Michaela Thoenes Alfredo Ramirez Klaus Fliessbach Clara Grezella Oliver Brüstle Michael Peitz Andreas Ebneth Alfredo Cabrera-Socorro

Stem Cell Res 2021 Apr 2;52:102180. Epub 2021 Feb 2.

Janssen Research & Development, Neuroscience Therapeutic Area (Johnson & Johnson), Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address:

APOE genotype is the strongest genetic risk factor for Alzheimer's Disease (AD). The low degree of homology between mouse and human APOE is a concerning issue in preclinical models currently used to study the role of this gene in AD pathophysiology. A key objective of ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) project was to generate in vitro models that better recapitulate human APOE biology. We describe a new set of induced pluripotent stem cells (iPSC) lines carrying common APOE variants (Ɛ2, Ɛ3, and Ɛ3/Ɛ4) and a knock-out isogenic to the parental APOE Ɛ4/Ɛ4 line (UKBi011-A).
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http://dx.doi.org/10.1016/j.scr.2021.102180DOI Listing
April 2021

[Role of Clinical, Sociomedical and Psychological Factors on Return to Work of Patients with Breast Cancer 6 Months after Rehabilitation].

Authors:
Oliver Rick Monika Reuß-Borst Timm Dauelsberg Holger G Hass Volker König Reiner Caspari Gabriele Götz-Keil Jürgen Pfitzner Christa Kerschgens Klaus Fliessbach Christian Hoppe

Rehabilitation (Stuttg) 2021 Jan 21. Epub 2021 Jan 21.

Klinik für Epileptologie, Universitätsklinik Bonn.

Aim Of The Study: The majority of patients with non-metastatic breast cancer return to work after tumor therapy. A rate of up to 80% is given in national and international studies, which can vary considerably depending on the study population and the various social systems. However, it is unclear how many patients are reintegrated into work after medical rehabilitation and which clinical, sociodemographic and psychological factors play a role.

Methods: In a multicentre study, clinical and sociodemographic data were collected from breast cancer patients at the beginning of their medical rehabilitation. Subjectively experienced deficits in attention performance (FEDA), depressive symptoms (PHQ-9) and health-related quality of life (EORTC QLQ-C30) were recorded using standardized questionnaires. The cognitive performance was also examined using a computer-based test battery (NeuroCog FX). A follow-up survey was carried out 6-9 months after medical rehabilitation. The subjective assessment of one's own cognitive performance (FEDA) was recorded again at this time.

Results: 396 of the originally 476 patients were included in the study. In the follow-up survey, 323/396 patients (82%) were again employed. In a regression model, sociodemographic factors proved to be particularly predictive with regard to occupational reintegration: employment at the time of the tumor diagnosis, job preserved after medical rehabilitation, employee status and gradual reintegration according to the Hamburg model (Nagelkerke R=0.685). This model could not be improved by adding psychological variables. The subjective patient information in all questionnaires was highly correlated (r>0.57; p<0.001).

Conclusion: The vast majority of breast cancer patients return to work after medical rehabilitation. Socio-demographic factors play a crucial role in this. The regression model developed here, including the employment status, professional orientation and gradual reintegration, is of predictive importance and can be used in medical rehabilitation.
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http://dx.doi.org/10.1055/a-1288-5824DOI Listing
January 2021

Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer's disease spectrum.

Authors:
Meret Herdick Martin Dyrba Hans-Christian J Fritz Slawek Altenstein Tommaso Ballarini Frederic Brosseron Katharina Buerger Arda Can Cetindag Peter Dechent Laura Dobisch Emrah Duezel Birgit Ertl-Wagner Klaus Fliessbach Silka Dawn Freiesleben Ingo Frommann Wenzel Glanz John Dylan Haynes Michael T Heneka Daniel Janowitz Ingo Kilimann Christoph Laske Coraline D Metzger Matthias H Munk Oliver Peters Josef Priller Nina Roy Klaus Scheffler Anja Schneider Annika Spottke Eike Jakob Spruth Maike Tscheuschler Ruth Vukovich Jens Wiltfang Frank Jessen Stefan Teipel Michel J Grothe

Neuroimage Clin 2020 11;28:102495. Epub 2020 Nov 11.

German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. Electronic address:

Background: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer's disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes.

Methods: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aβ42/40 biomarker data, which was available in a subset of participants.

Results: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aβ42/40 stratified analyses largely matched these results.

Conclusions: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry.
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http://dx.doi.org/10.1016/j.nicl.2020.102495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689403PMC
November 2020

Association between composite scores of domain-specific cognitive functions and regional patterns of atrophy and functional connectivity in the Alzheimer's disease spectrum.

Authors:
Chimezie O Amaefule Martin Dyrba Steffen Wolfsgruber Alexandra Polcher Anja Schneider Klaus Fliessbach Annika Spottke Dix Meiberth Lukas Preis Oliver Peters Enise I Incesoy Eike J Spruth Josef Priller Slawek Altenstein Claudia Bartels Jens Wiltfang Daniel Janowitz Katharina Bürger Christoph Laske Matthias Munk Janna Rudolph Wenzel Glanz Laura Dobisch John D Haynes Peter Dechent Birgit Ertl-Wagner Klaus Scheffler Ingo Kilimann Emrah Düzel Coraline D Metzger Michael Wagner Frank Jessen Stefan J Teipel

Neuroimage Clin 2021 17;29:102533. Epub 2020 Dec 17.

German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany.

Background: Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer's disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD.

Method: We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the AD-spectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD.

Result: Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum.

Conclusion: Consistent associations between cognitive domain scores and both regional atrophy and network-specific functional connectivity (except for the visual network), support the utility of a multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in the AD-spectrum.
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http://dx.doi.org/10.1016/j.nicl.2020.102533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770965PMC
December 2020

Abnormal Regional and Global Connectivity Measures in Subjective Cognitive Decline Depending on Cerebral Amyloid Status.

Authors:
Shumei Li Marcel Daamen Lukas Scheef Florian C Gaertner Ralph Buchert Martina Buchmann Katharina Buerger Cihan Catak Laura Dobisch Alexander Drzezga Birgit Ertl-Wagner Markus Essler Klaus Fliessbach John Dylan Haynes Enise Irem Incesoy Ingo Kilimann Bernd J Krause Catharina Lange Christoph Laske Josef Priller Alfredo Ramirez Matthias Reimold Axel Rominger Nina Roy Klaus Scheffler Angelika Maurer Anja Schneider Annika Spottke Eike Jakob Spruth Stefan J Teipel Maike Tscheuschler Michael Wagner Steffen Wolfsgruber Emrah Düzel Frank Jessen Oliver Peters Henning Boecker

J Alzheimers Dis 2021 ;79(2):493-509

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

Background: Amyloid-β accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer's continuum in the 2018 NIA-AA research framework.

Objective: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus.

Methods: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAβ+) and amyloidnegative SCD (SCDβ-) patients were selected according to visual [18F]-Florbetaben (FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVR=⫖FBB).

Results: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDAβ+patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAβ+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAβ+) and precuneus SUVRFBB (both groups).

Conclusion: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAβ+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-β load, highlighting incipient pathology in stage 2 of the AD continuum.
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http://dx.doi.org/10.3233/JAD-200472DOI Listing
January 2021

Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers-results from the DELCODE study.

Authors:
Lena Sannemann Ann-Katrin Schild Slawek Altenstein Claudia Bartels Frederic Brosseron Katharina Buerger Nicoleta Carmen Cosma Klaus Fliessbach Silka Dawn Freiesleben Wenzel Glanz Michael T Heneka Daniel Janowitz Ingo Kilimann Xenia Kobeleva Christoph Laske Coraline D Metzger Matthias H J Munk Robert Perneczky Oliver Peters Alexandra Polcher Josef Priller Boris Rauchmann Christina Rösch Janna Rudolph Anja Schneider Annika Spottke Eike Jakob Spruth Stefan Teipel Ruth Vukovich Michael Wagner Jens Wiltfang Steffen Wolfsgruber Emrah Duezel Frank Jessen

Alzheimers Res Ther 2020 10 16;12(1):131. Epub 2020 Oct 16.

Department of Psychiatry, Medical Faculty, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany.

Background: Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries.

Methods: We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries.

Results: The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996-1.000, p < .05).

Conclusion: These findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated with underlying AD pathology in cognitively unimpaired participants who worry about cognitive decline.

Trial Registration: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.
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http://dx.doi.org/10.1186/s13195-020-00701-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566134PMC
October 2020

Twenty-year follow-up of a pilot/phase II trial on the Bonn protocol for primary CNS lymphoma.

Authors:
Sabine Seidel Hendrik Pels Sabine Schlömer Annika Kowoll Klaus Fliessbach Andreas Engert Marlies Vogt-Schaden Gerlinde Egerer Heinz Reichmann Gabriele Schackert Frank Kroschinsky Martina Deckert Ulrich Herrlinger Thomas Klockgether Rolf Fimmers Udo Bode Ingo G H Schmidt-Wolf Uwe Schlegel

Neurology 2020 12 28;95(23):e3138-e3144. Epub 2020 Sep 28.

From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.

Objective: To determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years.

Methods: Sixty-five patients (median age 62 years, range 27-75; median Karnofsky performance score 70, range 20-90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation.

Results: Median follow-up for surviving patients was 19.6 years (17.5-23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9-5.9); for patients ≤60 years, 11.0 years (95% CI 4.8-17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years.

Conclusion: At a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL.

Classification Of Evidence: This work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.
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http://dx.doi.org/10.1212/WNL.0000000000010949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734926PMC
December 2020

Network Localization of Alien Limb in Patients with Corticobasal Syndrome.

Authors:
Aaron M Tetreault Tony Phan Kalen J Petersen Daniel O Claassen Byran J Neth Jonathan Graff-Radford Franziska Albrecht Klaus Fliessbach Anja Schneider Matthis Synofzik Janine Diehl-Schmid Markus Otto Matthias L Schroeter Richard Ryan Darby

Ann Neurol 2020 12 2;88(6):1118-1131. Epub 2020 Oct 2.

Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.

Objective: Perirolandic atrophy occurs in corticobasal syndrome (CBS) but is not specific versus progressive supranuclear palsy (PSP). There is heterogeneity in the locations of atrophy outside the perirolandic cortex and it remains unknown why atrophy in different locations would cause the same CBS-specific symptoms. In prior work, we used a wiring diagram of the brain called the human connectome to localize lesion-induced disorders to symptom-specific brain networks. Here, we use a similar technique termed "atrophy network mapping" to localize single-subject atrophy maps to symptom-specific brain networks.

Methods: Single-subject atrophy maps were generated by comparing cortical thickness in patients with CBS versus controls. Next, we performed seed-based functional connectivity using a large normative connectome to determine brain regions functionally connected to each patient's atrophied locations.

Results: Patients with CBS had perirolandic atrophy versus controls at the group level, but locations of atrophy in CBS were heterogeneous outside of the perirolandic cortex at the single-subject level (mean spatial correlation = 0.04). In contrast, atrophy occurred in locations functionally connected to the perirolandic cortex in all patients with CBS (spatial correlation = 0.66). Compared with PSP, patients with CBS had atrophy connected to a network of higher-order sensorimotor regions beyond perirolandic cortex, matching a CBS atrophy network from a recent meta-analysis. Finally, atrophy network mapping identified a symptom-specific network for alien limb, matching a lesion-induced alien limb network and a network associated with agency in healthy subjects.

Interpretation: We identified a syndrome-specific network for CBS and symptom-specific network for alien limb using single-subject atrophy maps and the human connectome. ANN NEUROL 2020;88:1118-1131.
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http://dx.doi.org/10.1002/ana.25901DOI Listing
December 2020

Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients.

Authors:
Sofia Finsterwalder Naomi Vlegels Benno Gesierich Miguel Á Araque Caballero Nick A Weaver Nicolai Franzmeier Marios K Georgakis Marek J Konieczny Huiberdina L Koek Celeste M Karch Neill R Graff-Radford Stephen Salloway Hwamee Oh Ricardo F Allegri Jasmeer P Chhatwal Frank Jessen Emrah Düzel Laura Dobisch Coraline Metzger Oliver Peters Enise I Incesoy Josef Priller Eike J Spruth Anja Schneider Klaus Fließbach Katharina Buerger Daniel Janowitz Stefan J Teipel Ingo Kilimann Christoph Laske Martina Buchmann Michael T Heneka Frederic Brosseron Annika Spottke Nina Roy Birgit Ertl-Wagner Klaus Scheffler Sang Won Seo Yeshin Kim Duk L Na Hee Jin Kim Hyemin Jang Michael Ewers Johannes Levin Reinhold Schmidt Ofer Pasternak Martin Dichgans Geert Jan Biessels Marco Duering

Alzheimers Dement 2020 11 18;16(11):1504-1514. Epub 2020 Aug 18.

Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany.

Introduction: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations.

Methods: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures.

Results: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant.

Discussion: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD.
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http://dx.doi.org/10.1002/alz.12150DOI Listing
November 2020

Minor neuropsychological deficits in patients with subjective cognitive decline.

Authors:
Steffen Wolfsgruber Luca Kleineidam Jannis Guski Alexandra Polcher Ingo Frommann Sandra Roeske Eike Jakob Spruth Christiana Franke Josef Priller Ingo Kilimann Stefan Teipel Katharina Buerger Daniel Janowitz Christoph Laske Martina Buchmann Oliver Peters Felix Menne Manuel Fuentes Casan Jens Wiltfang Claudia Bartels Emrah Düzel Coraline Metzger Wenzel Glanz Manuela Thelen Annika Spottke Alfredo Ramirez Barbara Kofler Klaus Fließbach Anja Schneider Michael T Heneka Frederic Brosseron Dix Meiberth Frank Jessen Michael Wagner

Neurology 2020 09 7;95(9):e1134-e1143. Epub 2020 Jul 7.

From the German Center for Neurodegenerative Diseases (S.W., L.K., J.G., A.P., I.F., S.R., M.T., A. Spottke, A.R., B.K., K.F., A. Schneider, M.H., F.B., D.M., F.J., M.W.); Department of Neurodegenerative Diseases and Geriatric Psychiatry (S.W., L.K., J.G., A.P., I.F., A.R., B.K., K.F., A. Schneider, M.T.H., F.B., M.W.), University of Bonn; German Center for Neurodegenerative Diseases (E.J.S., J.P., O.P., F.M., M.F.C.); Department of Psychiatry and Psychotherapy (E.J.S., C.F., J.P.), Charité-Universitätsmedizin Berlin; German Center for Neurodegenerative Diseases (I.K., S.T.); Department of Psychosomatic Medicine (I.K., S.T.), Rostock University Medical Center; German Center for Neurodegenerative Diseases (K.B.); Institute for Stroke and Dementia Research (K.B., D.J.), University Hospital, LMU Munich; German Center for Neurodegenerative Diseases (C.L., M.B.); Section for Dementia Research (C.L., M.B.), Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen; Charité-Universitätsmedizin Berlin (O.P., F.M., M.F.C.), corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin; (O.P., F.M., M.F.C.), Berlin Institute of Health, Institute of Psychiatry and Psychotherapy; German Center for Neurodegenerative Diseases (J.W., C.B.); Department of Psychiatry and Psychotherapy (J.W., C.B.), University Medical Center Goettingen, University of Goettingen; German Center for Neurodegenerative Diseases (E.D., C.M.); Institute of Cognitive Neurology and Dementia Research (E.D., C.M., W.G.) and Department of Psychiatry and Psychotherapy (C.M.), Otto-von-Guericke University, Magdeburg; Department of Neurology (A. Spottke), University Hospital Bonn; and Division of Neurogenetics and Molecular Psychiatry (A.R.) and Department of Psychiatry (M.T., D.M., F.J.), Medical Faculty University of Cologne, Germany.

Objective: To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with CSF biomarkers of Alzheimer disease (AD).

Method: We analyzed data from n = 449 cognitively normal participants (n = 209 healthy controls, n = 240 patients with SCD) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, 5 cognitive domain factor structure comprising learning and memory, executive functions, language abilities, working memory, and visuospatial functions. We compared groups in terms of global and domain-specific performance and correlated performance with different CSF markers of AD pathology.

Results: We observed worse performance (Cohen d = ≈0.25-0.5, adjusted for age, sex differences with analysis of covariance) in global performance, memory, executive functions, and language abilities for the SCD group compared to healthy controls. In addition, worse performance in these domains was moderately ( = ≈0.3) associated with lower CSF β-amyloid and CSF β-amyloid/phosphorylated tau181 in the whole sample and specifically in the SCD subgroup.

Conclusions: Within the spectrum of clinically unimpaired (i.e., before mild cognitive impairment) cognitive performance, SCD is associated with minor deficits in memory, executive function, and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD.
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http://dx.doi.org/10.1212/WNL.0000000000010142DOI Listing
September 2020

One-Stop Shop: F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases.

Authors:
Jochen Hammes Gérard N Bischof Karl P Bohn Özgür Onur Anja Schneider Klaus Fliessbach Merle C Hönig Frank Jessen Bernd Neumaier Alexander Drzezga Thilo van Eimeren

J Nucl Med 2021 Feb 3;62(2):240-246. Epub 2020 Jul 3.

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

Tau protein aggregations are a hallmark of amyloid-associated Alzheimer disease and some forms of non-amyloid-associated frontotemporal lobar degeneration. In recent years, several tracers for in vivo tau imaging have been under evaluation. This study investigated the ability of F-flortaucipir PET not only to assess tau positivity but also to differentiate between amyloid-positive and -negative forms of neurodegeneration on the basis of different F-flortaucipir PET signatures. The F-flortaucipir PET data of 35 patients with amyloid-positive neurodegeneration, 19 patients with amyloid-negative neurodegeneration, and 17 healthy controls were included in a data-driven scaled subprofile model (SSM)/principal-component analysis (PCA) identifying spatial covariance patterns. SSM/PCA pattern expression strengths were tested for their ability to predict amyloid status in a receiver-operating-characteristic analysis and validated with a leave-one-out approach. Pattern expression strengths predicted amyloid status with a sensitivity of 0.94 and a specificity of 0.83. A support vector machine classification based on pattern expression strengths in 2 different SSM/PCA components yielded a prediction accuracy of 98%. Anatomically, prediction performance was driven by parietooccipital gray matter in amyloid-positive patients versus predominant white matter binding in amyloid-negative patients. SSM/PCA-derived binding patterns of F-flortaucipir differentiate between amyloid-positive and -negative neurodegenerative diseases with high accuracy. F-flortaucipir PET alone may convey additional information equivalent to that from amyloid PET. Together with a perfusion-weighted early-phase acquisition (F-FDG PET-equivalent), a single scan potentially contains comprehensive information on amyloid (A), tau (T), and neurodegeneration (N) status as required by recent biomarker classification algorithms (A/T/N).
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http://dx.doi.org/10.2967/jnumed.120.244061DOI Listing
February 2021

Bupropion for the Treatment of Apathy in Alzheimer Disease: A Randomized Clinical Trial.

Authors:
Franziska Maier Annika Spottke Jan-Philipp Bach Claudia Bartels Katharina Buerger Richard Dodel Andreas Fellgiebel Klaus Fliessbach Lutz Frölich Lucrezia Hausner Martin Hellmich Stefan Klöppel Arne Klostermann Johannes Kornhuber Christoph Laske Oliver Peters Josef Priller Tanja Richter-Schmidinger Anja Schneider Kija Shah-Hosseini Stefan Teipel Christine A F von Arnim Jens Wiltfang Frank Jessen

JAMA Netw Open 2020 05 1;3(5):e206027. Epub 2020 May 1.

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

Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed.

Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type.

Design, Setting, And Participants: This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019.

Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study.

Main Outcomes And Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks.

Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups.

Conclusions And Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood.

Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.6027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256670PMC
May 2020

Advanced glycation end products and protein carbonyl levels in plasma reveal sex-specific differences in Parkinson's and Alzheimer's disease.

Authors:
Amit Sharma Daniela Weber Jana Raupbach Tikam Chand Dakal Klaus Fließbach Alfredo Ramirez Tilman Grune Ullrich Wüllner

Redox Biol 2020 07 18;34:101546. Epub 2020 May 18.

Department of Neurology, University Clinic Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. Electronic address:

Neurodegenerative diseases (NDD) such as Alzheimer's (AD) and Parkinson's disease (PD) are distinct clinical entities, however, the aggregation of key neuronal proteins, presumably leading to neuronal demise appears to represent a common mechanism. It has become evident, that advanced glycation end products (AGEs) trigger the accumulation of such modified proteins, which eventually contributes to pathological aspect of NDDs. Increased levels of AGEs are found in amyloid plaques in AD brains and in both advanced and early PD (incidental Lewy body disease). The molecular mechanisms by which AGE dependent modifications may modulate the susceptibility towards NDDs, however, remain enigmatic and it is unclear, whether AGEs may serve as biomarker of NDD. In the present study, we examined AGEs (CML: Carboxymethyllysine and CEL: Carboxyethyllysine), markers of oxidative stress and micronutrients in the plasma of PD and AD patients and controls. As compared to healthy controls, AD females displayed lower levels of CEL while higher levels of CML were found in AD and PD patients. A somewhat similar pattern was observed for protein carbonyls (PC), revealing lower values exclusively in AD females, whereas AD males displayed significantly higher values compared to healthy controls and PD. Sex-specific differences were also observed for other relevant markers such as malondialdehyde, 3-nitrotyrosine, γ -tocopherols, retinol, plasma proteins and α-carotene, while α-tocopherols, β-carotene, lutein/zeaxanthin, β-cryptoxanthin and lycopene showed no relevant association. Taken together, our study suggests yet unappreciated differences of the distribution of AGEs among the sexes in NDD. We therefore suggest to make a clear distinction between sexes when analyzing oxidative (AGEs)-related stress and carbonyl-related stress and vitamins.
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http://dx.doi.org/10.1016/j.redox.2020.101546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251371PMC
July 2020

Disentangling brain functional network remodeling in corticobasal syndrome - A multimodal MRI study.

Authors:
Tommaso Ballarini Franziska Albrecht Karsten Mueller Robert Jech Janine Diehl-Schmid Klaus Fliessbach Jan Kassubek Martin Lauer Klaus Fassbender Anja Schneider Matthis Synofzik Jens Wiltfang Markus Otto Matthias L Schroeter

Neuroimage Clin 2020 2;25:102112. Epub 2019 Dec 2.

Max Planck Institute for Human Cognitive and Brain Sciences Leipzig, Germany; Clinic for Cognitive Neurology, University Clinic, Leipzig, Germany.

Objective: The clinical diagnosis of corticobasal syndrome (CBS) represents a challenge for physicians and reliable diagnostic imaging biomarkers would support the diagnostic work-up. We aimed to investigate the neural signatures of CBS using multimodal T1-weighted and resting-state functional magnetic resonance imaging (MRI).

Methods: Nineteen patients with CBS (age 67.0 ± 6.0 years; mean±SD) and 19 matched controls (66.5 ± 6.0) were enrolled from the German Frontotemporal Lobar Degeneration Consortium. Changes in functional connectivity and structure were respectively assessed with eigenvector centrality mapping complemented by seed-based analysis and with voxel-based morphometry. In addition to mass-univariate statistics, multivariate support vector machine (SVM) classification tested the potential of multimodal MRI to differentiate patients and controls. External validity of SVM was assessed on independent CBS data from the 4RTNI database.

Results: A decrease in brain interconnectedness was observed in the right central operculum, middle temporal gyrus and posterior insula, while widespread connectivity increases were found in the anterior cingulum, medial superior-frontal gyrus and in the bilateral caudate nuclei. Severe and diffuse gray matter volume reduction, especially in the bilateral insula, putamen and thalamus, characterized CBS. SVM classification revealed that both connectivity (area under the curve 0.81) and structural abnormalities (0.80) distinguished CBS from controls, while their combination led to statistically non-significant improvement in discrimination power, questioning the additional value of functional connectivity over atrophy. SVM analyses based on structural MRI generalized moderately well to new data, which was decisively improved when guided by meta-analytically derived disease-specific regions-of-interest.

Conclusions: Our data-driven results show impairment of functional connectivity and brain structure in CBS and explore their potential as imaging biomarkers.
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http://dx.doi.org/10.1016/j.nicl.2019.102112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906725PMC
January 2021

Cognitive Performance and Psychological Distress in Breast Cancer Patients at Disease Onset.

Authors:
Jochen Kaiser Jörg Dietrich Miena Amiri Isa Rüschel Hazal Akbaba Nonda Hantke Klaus Fliessbach Bianca Senf Christine Solbach Christoph Bledowski

Front Psychol 2019 15;10:2584. Epub 2019 Nov 15.

Institute of Medical Psychology, Goethe University Frankfurt, Frankfurt am Main, Germany.

Objective: Many cancer patients complain about cognitive dysfunction. While cognitive deficits have been attributed to the side effects of chemotherapy, there is evidence for impairment at disease onset, prior to cancer-directed therapy. Further debated issues concern the relationship between self-reported complaints and objective test performance and the role of psychological distress.

Method: We assessed performance on neuropsychological tests of attention and memory and obtained estimates of subjective distress and quality of life in 27 breast cancer patients and 20 healthy controls. Testing in patients took place shortly after the initial diagnosis, but prior to subsequent therapy.

Results: While patients showed elevated distress, cognitive performance differed on a few subtests only. Patients showed slower processing speed and poorer verbal memory than controls. Objective and self-reported cognitive function were unrelated, and psychological distress correlated more strongly with subjective complaints than with neuropsychological test performance.

Conclusion: This study provides further evidence of limited cognitive deficits in cancer patients prior to the onset of adjuvant therapy. Self-reported cognitive deficits seem more closely related to psychological distress than to objective test performance.
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http://dx.doi.org/10.3389/fpsyg.2019.02584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873390PMC
November 2019

Multicenter Tract-Based Analysis of Microstructural Lesions within the Alzheimer's Disease Spectrum: Association with Amyloid Pathology and Diagnostic Usefulness.

Authors:
Stefan J Teipel Jan O Kuper-Smith Claudia Bartels Frederic Brosseron Martina Buchmann Katharina Buerger Cihan Catak Daniel Janowitz Peter Dechent Laura Dobisch Birgit Ertl-Wagner Klaus Fließbach John-Dylan Haynes Michael T Heneka Ingo Kilimann Christoph Laske Siyao Li Felix Menne Coraline D Metzger Josef Priller Verena Pross Alfredo Ramirez Klaus Scheffler Anja Schneider Annika Spottke Eike J Spruth Michael Wagner Jens Wiltfang Steffen Wolfsgruber Emrah Düzel Frank Jessen Martin Dyrba

J Alzheimers Dis 2019 ;72(2):455-465

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

Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer's disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis (p < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aβ positive MCI cases from Aβ negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aβ positive SCD and control cases from Aβ negative controls. These findings suggest that in prodromal stages of AD, such as in Aβ positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aβ positive SCD and control cases.
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http://dx.doi.org/10.3233/JAD-190446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918918PMC
November 2020

Higher CSF Tau Levels Are Related to Hippocampal Hyperactivity and Object Mnemonic Discrimination in Older Adults.

Authors:
David Berron Arturo Cardenas-Blanco Daniel Bittner Coraline D Metzger Annika Spottke Michael T Heneka Klaus Fliessbach Anja Schneider Stefan J Teipel Michael Wagner Oliver Speck Frank Jessen Emrah Düzel

J Neurosci 2019 10 20;39(44):8788-8797. Epub 2019 Sep 20.

Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, 39120 Magdeburg, Germany.

Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTLs). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination, even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC), have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance, and levels of total and phosphorylated tau as well as Aβ42/40 ratio in CSF. We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus, and both increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects, but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline. Subregions in the human medial temporal lobe are critically involved in episodic memory and, at the same time, affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals, but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related fMRI in combination with measures of tau pathology in CSF, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.
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http://dx.doi.org/10.1523/JNEUROSCI.1279-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820211PMC
October 2019

Memorability of photographs in subjective cognitive decline and mild cognitive impairment: Implications for cognitive assessment.

Authors:
Wilma A Bainbridge David Berron Hartmut Schütze Arturo Cardenas-Blanco Coraline Metzger Laura Dobisch Daniel Bittner Wenzel Glanz Annika Spottke Janna Rudolph Frederic Brosseron Katharina Buerger Daniel Janowitz Klaus Fliessbach Michael Heneka Christoph Laske Martina Buchmann Oliver Peters Dominik Diesing Siyao Li Josef Priller Eike Jakob Spruth Slawek Altenstein Anja Schneider Barbara Kofler Stefan Teipel Ingo Kilimann Jens Wiltfang Claudia Bartels Steffen Wolfsgruber Michael Wagner Frank Jessen Chris I Baker Emrah Düzel

Alzheimers Dement (Amst) 2019 Dec 5;11:610-618. Epub 2019 Sep 5.

Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

Introduction: Impaired long-term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently memorable.

Methods: We conducted item-based analyses of long-term visual recognition memory. Three hundred ninety-four participants (healthy controls, subjective cognitive decline [SCD], and MCI) in the multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs.

Results: We observed consistent memorability for images in healthy controls, SCD, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set.

Discussion: Individuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.
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http://dx.doi.org/10.1016/j.dadm.2019.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732671PMC
December 2019

A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2.

Authors:
Meliha Karsak Konstantin Glebov Marina Scheffold Thomas Bajaj Amit Kawalia Ilker Karaca Sebastian Rading Johannes Kornhuber Oliver Peters Monica Diez-Fairen Lutz Frölich Michael Hüll Jens Wiltfang Martin Scherer Steffi Riedel-Heller Anja Schneider Michael T Heneka Klaus Fliessbach Ahmed Sharaf Holger Thiele Martina Lennarz Frank Jessen Wolfgang Maier Christian Kubisch Zoya Ignatova Peter Nürnberg Pau Pastor Jochen Walter Alfredo Ramirez

Hum Mutat 2020 01 15;41(1):169-181. Epub 2019 Sep 15.

Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany.

Rare coding variants in the triggering receptor expressed on myeloid cells-2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss-of-function variants have been reported in families with monogenic frontotemporal-like dementia with/without bone abnormalities. In a whole-exome sequencing study of a family with probable AD-type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) ε4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine-to-tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G>T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin-like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)-induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD-like form of dementia.
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http://dx.doi.org/10.1002/humu.23904DOI Listing
January 2020

MR fingerprinting as a diagnostic tool in patients with frontotemporal lobe degeneration: A pilot study.

Authors:
Vera Catharina Keil Stilyana Peteva Bakoeva Alina Jurcoane Mariya Doneva Thomas Amthor Peter Koken Burkhard Mädler Wolfgang Block Rolf Fimmers Klaus Fliessbach Elke Hattingen

NMR Biomed 2019 11 8;32(11):e4157. Epub 2019 Aug 8.

Department of Radiology, University Hospital Bonn, Venusberg Campus 1, Bonn, Germany.

Several very rare forms of dementia are associated with characteristic focal atrophy predominantly of the frontal and/or temporal lobes and currently lack imaging solutions to monitor disease. Magnetic resonance fingerprinting (MRF) is a recently developed technique providing quantitative relaxivity maps and images with various tissue contrasts out of a single sequence acquisition. This pilot study explores the utility of MRF-based T1 and T2 mapping to discover focal differences in relaxation times between patients with frontotemporal lobe degenerative dementia and healthy controls. 8 patients and 30 healthy controls underwent a 3 T MRI including an axial 2D spoiled gradient echo MRF sequence. T1 and T2 relaxation maps were generated based on an extended phase graphs algorithm-founded dictionary involving inner product pattern matching. A region of interest (ROI)-based analysis of T1 and T2 relaxation times was performed with FSL and ITK-SNAP. Depending on the brain region analyzed, T1 relaxation times were up to 10.28% longer in patients than in controls reaching significant differences in cortical gray matter (P = .047) and global white matter (P = .023) as well as in both hippocampi (P = .001 left; P = .027 right). T2 relaxation times were similarly longer in the hippocampus by up to 19.18% in patients compared with controls. The clinically most affected patient had the most control-deviant relaxation times. There was a strong correlation of T1 relaxation time in the amygdala with duration of the clinically manifest disease (Spearman Rho = .94; P = .001) and of T1 relaxation times in the left hippocampus with disease severity (Rho = .90, P = .002). In conclusion, MRF-based relaxometry is a promising and time-saving new MRI tool to study focal cerebral alterations and identify patients with frontotemporal lobe degeneration. To validate the results of this pilot study, MRF is worth further exploration as a diagnostic tool in neurodegenerative diseases.
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http://dx.doi.org/10.1002/nbm.4157DOI Listing
November 2019

Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study.

Authors:
Lisa Miebach Steffen Wolfsgruber Alexandra Polcher Oliver Peters Felix Menne Katja Luther Enise Incesoy Josef Priller Eike Spruth Slawek Altenstein Katharina Buerger Cihan Catak Daniel Janowitz Robert Perneczky Julia Utecht Christoph Laske Martina Buchmann Anja Schneider Klaus Fliessbach Pascal Kalbhen Michael T Heneka Frederic Brosseron Annika Spottke Nina Roy Stefan J Teipel Ingo Kilimann Jens Wiltfang Claudia Bartels Emrah Düzel Laura Dobisch Coraline Metzger Dix Meiberth Alfredo Ramirez Frank Jessen Michael Wagner

Alzheimers Res Ther 2019 07 31;11(1):66. Epub 2019 Jul 31.

German Center for Neurodegenerative Diseases/Clinical Research, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Zentrum für klinische Forschung/AG Neuropsychologie, Sigmund-Freud-Str. 27, 53127, Bonn, Germany.

Background: Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer's disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers.

Methods: We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers.

Results: Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181.

Conclusions: Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.
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http://dx.doi.org/10.1186/s13195-019-0515-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668160PMC
July 2019

[Anti-tau therapies-what can be expected?]

Authors:
Klaus Fließbach Cornelia McCormick Barbara Kaulen Anja Schneider

Nervenarzt 2019 Sep;90(9):891-897

Klinik für Neurodegenerative Erkrankungen und Gerontopsychiatrie, Universitätsklinikum Bonn Venusberg, Campus 1, 53127, Bonn, Deutschland.

Alzheimer's disease is histopathologically characterized by aggregation of two proteins, namely amyloid-beta peptide and tau protein. Whereas former intervention trials focused particularly on the amyloid pathology, recent therapeutic approaches are directed against the tau pathology. This article summarizes recent progress in anti-tau therapies, especially therapies based on anti-tau immunization and antisense oligonucleotides (ASO).
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http://dx.doi.org/10.1007/s00115-019-0758-7DOI Listing
September 2019

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases.

Authors:
Matthew J Betts Evgeniya Kirilina Maria C G Otaduy Dimo Ivanov Julio Acosta-Cabronero Martina F Callaghan Christian Lambert Arturo Cardenas-Blanco Kerrin Pine Luca Passamonti Clare Loane Max C Keuken Paula Trujillo Falk Lüsebrink Hendrik Mattern Kathy Y Liu Nikos Priovoulos Klaus Fliessbach Martin J Dahl Anne Maaß Christopher F Madelung David Meder Alexander J Ehrenberg Oliver Speck Nikolaus Weiskopf Raymond Dolan Ben Inglis Duygu Tosun Markus Morawski Fabio A Zucca Hartwig R Siebner Mara Mather Kamil Uludag Helmut Heinsen Benedikt A Poser Robert Howard Luigi Zecca James B Rowe Lea T Grinberg Heidi I L Jacobs Emrah Düzel Dorothea Hämmerer

Brain 2019 09;142(9):2558-2571

Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.
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http://dx.doi.org/10.1093/brain/awz193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736046PMC
September 2019

Structural integrity in subjective cognitive decline, mild cognitive impairment and Alzheimer's disease based on multicenter diffusion tensor imaging.

Authors:
Katharina Brueggen Martin Dyrba Arturo Cardenas-Blanco Anja Schneider Klaus Fliessbach Katharina Buerger Daniel Janowitz Oliver Peters Felix Menne Josef Priller Eike Spruth Jens Wiltfang Ruth Vukovich Christoph Laske Martina Buchmann Michael Wagner Sandra Röske Annika Spottke Janna Rudolph Coraline D Metzger Ingo Kilimann Laura Dobisch Emrah Düzel Frank Jessen Stefan J Teipel

J Neurol 2019 Oct 21;266(10):2465-2474. Epub 2019 Jun 21.

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

Introduction: Subjective cognitive decline (SCD) can represent a preclinical stage of Alzheimer's disease. Diffusion tensor imaging (DTI) could aid an early diagnosis, yet only few monocentric DTI studies in SCD have been conducted, reporting heterogeneous results. We investigated microstructural changes in SCD in a larger, multicentric cohort.

Methods: 271 participants with SCD, mild cognitive impairment (MCI) or Alzheimer's dementia (AD) and healthy controls (CON) were included, recruited prospectively at nine centers of the observational DELCODE study. DTI was acquired using identical protocols. Using voxel-based analyses, we investigated fractional anisotropy (FA), mean diffusivity (MD) and mode (MO) in the white matter (WM). Discrimination accuracy was determined by cross-validated elastic-net penalized regression. Center effects were explored using variance analyses.

Results: MO and FA were lower in SCD compared to CON in several anterior and posterior WM regions, including the anterior corona radiata, superior and inferior longitudinal fasciculus, cingulum and splenium of the corpus callosum (p < 0.01, uncorrected). MD was higher in the superior and inferior longitudinal fasciculus, cingulum and superior corona radiata (p < 0.01, uncorrected). The cross-validated accuracy for discriminating SCD from CON was 67% (p < 0.01). As expected, the AD and MCI groups had higher MD and lower FA and MO in extensive regions, including the corpus callosum and temporal brain regions. Within these regions, center accounted for 3-15% of the variance.

Conclusions: DTI revealed subtle WM alterations in SCD that were intermediate between those in MCI and CON and may be useful to detect individuals with an increased risk for AD in clinical studies.
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http://dx.doi.org/10.1007/s00415-019-09429-3DOI Listing
October 2019

Level of education mitigates the impact of tau pathology on neuronal function.

Authors:
Merle C Hoenig Gérard N Bischof Özgür A Onur Juraj Kukolja Frank Jessen Klaus Fliessbach Bernd Neumaier Gereon R Fink Elke Kalbe Alexander Drzezga Thilo van Eimeren

Eur J Nucl Med Mol Imaging 2019 Aug 10;46(9):1787-1795. Epub 2019 Jun 10.

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

Purpose: Using PET imaging in a group of patients with Alzheimer's disease (AD), we investigated whether level of education, a proxy for resilience, mitigates the harmful impact of tau pathology on neuronal function.

Methods: We included 38 patients with mild-to-moderate AD (mean age 67 ± 7 years, mean MMSE score 24 ± 4, mean years of education 14 ± 4; 20 men, 18 women) in whom a [F]AV-1451 scan (a measure of tau pathology) and an [F]FDG scan (a measure of neuronal function) were available. The preprocessed PET scans were z-transformed using templates for [F]AV-1451 and [F]FDG from healthy controls, and subsequently thresholded at a z-score of ≥3.0, representing an one-tailed p value of 0.001. Next, three volumes were computed in each patient: the tau-specific volume (tau pathology without neuronal dysfunction), the FDG-specific volume (neuronal dysfunction without tau pathology), and the overlap volume (tau pathology and neuronal dysfunction). Mean z-scores and volumes were extracted and used as dependent variables in regression analysis with years of education as predictor, and age and MMSE score as covariates.

Results: Years of education were positively associated with tau-specific volume (β = 0.362, p = 0.022), suggesting a lower impact of tau pathology on neuronal function in patients with higher levels of education. Concomitantly, level of education was positively related to tau burden in the overlap volume (β = 0.303, p = 0.036) implying that with higher levels of education more tau pathology is necessary to induce neuronal dysfunction.

Conclusion: In patients with higher levels of education, tau pathology is less paralleled by regional and remote neuronal dysfunction. The data suggest that early life-time factors such as level of education support resilience mechanisms, which ameliorate AD-related effects later in life.
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http://dx.doi.org/10.1007/s00259-019-04342-3DOI Listing
August 2019

Computed-tomography-guided biopsy in suspected spondylodiscitis: Single-center experience including 201 biopsy procedures.

Authors:
Derya Özmen Neriman Özkan Nika Guberina Klaus Fliessbach Saravanabavaan Suntharalingam Jens Theysohn Matthias Büchter Michael Forsting Jan Buer Marcel Dudda Marcus Jäger Axel Wetter

Orthop Rev (Pavia) 2019 Feb 22;11(1):7793. Epub 2019 Mar 22.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen.

Our propose is to evaluate CT-guided biopsies in suspected spondylodiscitis with respect to puncture site, microbiology findings, histopathology findings and impact on antibiotic therapy. 86 CT-guided spine interventions in suspected spondylodiscitis comprising 201 biopsy procedures were analyzed. Medical records of all patients were screened for microbiology and histopathology reports as well as date, duration and kind of antibiotic therapy. Statistical analyses included calculation of Chi-tests and logistic regression analyses. Locations of biopsies were intervertebral disc (48.3%), paravertebral soft-tissue (38.3%) and vertebral body (10.9%). Positive microbiological findings were found altogether in 33.8% of cases, positive histopathological findings in 53.6%. Significant associations between positive microbiological findings, positive histopathological findings and antibiotic therapy, respectively, were found. Location of biopsies did not significantly influence rate of positive findings. From the variables age, white blood cell count, serum creatinine and puncture site, none were found to be an independent predictor for a positive microbiological result. We concluded that CT-guided biopsy of intervertebral disc and paravertebral soft tissue yields positive microbiologic findings in a significant proportion of cases. Puncture site is not associated with positive results of microbiology or histopathology.
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http://dx.doi.org/10.4081/or.2019.7793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452088PMC
February 2019

Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging.

Authors:
Franziska Albrecht Karsten Mueller Tommaso Ballarini Leonie Lampe Janine Diehl-Schmid Klaus Fassbender Klaus Fliessbach Holger Jahn Robert Jech Jan Kassubek Johannes Kornhuber Bernhard Landwehrmeyer Martin Lauer Albert C Ludolph Epameinondas Lyros Johannes Prudlo Anja Schneider Matthis Synofzik Jens Wiltfang Adrian Danek Markus Otto Matthias L Schroeter

Cortex 2019 08 25;117:33-40. Epub 2019 Feb 25.

Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Clinic of Cognitive Neurology, University of Leipzig, Germany; FTLD Consortium Germany, Germany.

Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure-function relationship of alien/anarchic limb was investigated in multi-centric structural magnetic resonance imaging (MRI) data. Whole-group and single-subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture.
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http://dx.doi.org/10.1016/j.cortex.2019.02.015DOI Listing
August 2019

The BDNF SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease.

Authors:
Nicolai Franzmeier Jinyi Ren Alexander Damm Gemma Monté-Rubio Mercè Boada Agustín Ruiz Alfredo Ramirez Frank Jessen Emrah Düzel Octavio Rodríguez Gómez Tammie Benzinger Alison Goate Celeste M Karch Anne M Fagan Eric McDade Katharina Buerger Johannes Levin Marco Duering Martin Dichgans Marc Suárez-Calvet Christian Haass Brian A Gordon Yen Ying Lim Colin L Masters Daniel Janowitz Cihan Catak Steffen Wolfsgruber Michael Wagner Esther Milz Sonia Moreno-Grau Stefan Teipel Michel J Grothe Ingo Kilimann Martin Rossor Nick Fox Christoph Laske Jasmeer Chhatwal Peter Falkai Robert Perneczky Jae-Hong Lee Annika Spottke Henning Boecker Frederic Brosseron Klaus Fliessbach Michael T Heneka Peter Nestor Oliver Peters Manuel Fuentes Felix Menne Josef Priller Eike J Spruth Christiana Franke Anja Schneider Christine Westerteicher Oliver Speck Jens Wiltfang Claudia Bartels Miguel Ángel Araque Caballero Coraline Metzger Daniel Bittner Stephen Salloway Adrian Danek Jason Hassenstab Igor Yakushev Peter R Schofield John C Morris Randall J Bateman Michael Ewers

Mol Psychiatry 2021 02 21;26(2):614-628. Epub 2019 Mar 21.

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.

In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNF an important modulating factor of cognitive impairment in AD. However, the effect of BDNF on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNF on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNF carriers compared to BDNF homozogytes. BDNF was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNF could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNF was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNF is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.
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http://dx.doi.org/10.1038/s41380-019-0404-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754794PMC
February 2021

FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations.

Authors:
Janine Diehl-Schmid Abigail Licata Oliver Goldhardt Hans Förstl Igor Yakushew Markus Otto Sarah Anderl-Straub Ambros Beer Albert Christian Ludolph Georg Bernhard Landwehrmeyer Johannes Levin Adrian Danek Klaus Fliessbach Annika Spottke Klaus Fassbender Epameinondas Lyros Johannes Prudlo Bernd Joachim Krause Alexander Volk Dieter Edbauer Matthias Leopold Schroeter Alexander Drzezga Johannes Kornhuber Martin Lauer Timo Grimmer

Transl Psychiatry 2019 01 31;9(1):54. Epub 2019 Jan 31.

Department of Psychiatry, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.
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http://dx.doi.org/10.1038/s41398-019-0381-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355852PMC
January 2019