| Literature DB >> 30899092 |
Nicolai Franzmeier1, Jinyi Ren1, Alexander Damm1, Gemma Monté-Rubio2, Mercè Boada2,3, Agustín Ruiz2,3, Alfredo Ramirez4,5, Frank Jessen4,6, Emrah Düzel7, Octavio Rodríguez Gómez2,3, Tammie Benzinger8,9, Alison Goate10,11, Celeste M Karch9,12,13, Anne M Fagan9,12,14, Eric McDade14, Katharina Buerger1,15, Johannes Levin15,16, Marco Duering1, Martin Dichgans1,15,17, Marc Suárez-Calvet15,18,19, Christian Haass15,19, Brian A Gordon9,20,21, Yen Ying Lim22, Colin L Masters22, Daniel Janowitz1, Cihan Catak1, Steffen Wolfsgruber5,6, Michael Wagner5,6, Esther Milz4, Sonia Moreno-Grau2,3, Stefan Teipel23,24, Michel J Grothe23, Ingo Kilimann23, Martin Rossor25, Nick Fox25, Christoph Laske26,27, Jasmeer Chhatwal28, Peter Falkai29, Robert Perneczky15,17,29,30, Jae-Hong Lee31, Annika Spottke6,32, Henning Boecker6,33, Frederic Brosseron5,6, Klaus Fliessbach5,6, Michael T Heneka5,6, Peter Nestor7,34, Oliver Peters35,36, Manuel Fuentes35,36, Felix Menne35,36, Josef Priller35,37, Eike J Spruth35,37, Christiana Franke35,37, Anja Schneider5,6, Christine Westerteicher5,6, Oliver Speck7,38,39,40, Jens Wiltfang41,42,43, Claudia Bartels42, Miguel Ángel Araque Caballero1,15, Coraline Metzger7, Daniel Bittner7, Stephen Salloway44, Adrian Danek16, Jason Hassenstab14, Igor Yakushev45, Peter R Schofield46,47, John C Morris9,13,14, Randall J Bateman9,14, Michael Ewers48.
Abstract
In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met 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 BDNFVal66Met 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 BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met 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 BDNFVal66Met 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, BDNFVal66Met 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 BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.Entities:
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Year: 2019 PMID： 30899092 PMCID： PMC6754794 DOI： 10.1038/s41380-019-0404-6
Source DB: PubMed Journal: Mol Psychiatry ISSN： 1359-4184 Impact factor: 15.992