Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany; Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany; Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Karsten Mueller
Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
Leonhard Schilbach
LVR-Klinikum Düsseldorf, Düsseldorf, Germany; Medical Faculty, Ludwig-Maximilians-Universität, München, Germany
Henryk Barthel
Department for Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany
Department of Neurology, Saarland University Hospital, Homburg, Germany
Klaus Fliessbach
Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Johannes Kornhuber
Department of Psychiatry and Psychotherapy, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
Johannes Prudlo
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurology, University Medicine Rostock, Rostock, Germany
Matthis Synofzik
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany
Jens Wiltfang
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Medical University Göttingen, Göttingen, Germany; Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
Janine Diehl-Schmid
Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany; kbo-Inn-Salzach-Klinikum, Clinical Center for Psychiatry, Psychotherapy, Psychosomatic Medicine, Geriatrics and Neurology, Wasserburg/Inn, Germany
FTLD Consortium
Markus Otto
Department of Neurology, Ulm University, Ulm, Germany; Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany; Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Matthias L Schroeter
Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Clinic for Cognitive Neurology, University Hospital Leipzig, Leipzig, Germany
Background: Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels. Methods: Maps of fractional amplitude of low-frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 females) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 females). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of co-localization is associated with the observed clinical symptoms. Results: Patients displayed significantly reduced fALFF in frontotemporal and frontoparietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b and 5-HT2a) and γ-aminobutyric acid type A (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with NET was associated with cognitive symptoms and disease severity of bvFTD. Conclusions: Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD. Funding: This study has been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (BMBF; grant no. FKZ01GI1007A).
