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Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems. 2024

Lisa Hahn, and Simon B Eickhoff, and Karsten Mueller, and Leonhard Schilbach, and Henryk Barthel, and Klaus Fassbender, and Klaus Fliessbach, and Johannes Kornhuber, and Johannes Prudlo, and Matthis Synofzik, and Jens Wiltfang, and Janine Diehl-Schmid, and , and Markus Otto, and Juergen Dukart, and Matthias L Schroeter
Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany.

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. 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. 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. 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. 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).

UI MeSH Term Description Entries
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D005260 Female Females
D005680 gamma-Aminobutyric Acid The most common inhibitory neurotransmitter in the central nervous system. 4-Aminobutyric Acid,GABA,4-Aminobutanoic Acid,Aminalon,Aminalone,Gammalon,Lithium GABA,gamma-Aminobutyric Acid, Calcium Salt (2:1),gamma-Aminobutyric Acid, Hydrochloride,gamma-Aminobutyric Acid, Monolithium Salt,gamma-Aminobutyric Acid, Monosodium Salt,gamma-Aminobutyric Acid, Zinc Salt (2:1),4 Aminobutanoic Acid,4 Aminobutyric Acid,Acid, Hydrochloride gamma-Aminobutyric,GABA, Lithium,Hydrochloride gamma-Aminobutyric Acid,gamma Aminobutyric Acid,gamma Aminobutyric Acid, Hydrochloride,gamma Aminobutyric Acid, Monolithium Salt,gamma Aminobutyric Acid, Monosodium Salt
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000368 Aged A person 65 years of age or older. For a person older than 79 years, AGED, 80 AND OVER is available. Elderly
D000588 Amines A group of compounds derived from ammonia by substituting organic radicals for the hydrogens. (From Grant & Hackh's Chemical Dictionary, 5th ed) Amine
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D012701 Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid L-TRYPTOPHAN. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (RECEPTORS, SEROTONIN) explain the broad physiological actions and distribution of this biochemical mediator. 5-HT,5-Hydroxytryptamine,3-(2-Aminoethyl)-1H-indol-5-ol,Enteramine,Hippophaine,Hydroxytryptamine,5 Hydroxytryptamine
D050484 Norepinephrine Plasma Membrane Transport Proteins Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of noradrenergic neurons. They remove NOREPINEPHRINE from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS. The norepinephrine transporter regulates signal amplitude and duration at noradrenergic synapses and is the target of ADRENERGIC UPTAKE INHIBITORS. Neurotransmitter Transporters, Noradrenaline-Specific,Norepinephrine Plasma Membrane Transporter Proteins,Norepinephrine Plasma Membrane Transporters,NET Protein, Neuronal,Noradrenaline Plasma Membrane Transport Proteins,Noradrenaline Transporter,Norepinephrine Transporter,Norepinephrine Transporter Protein,SLC6A2 Protein,Sodium-Dependent Noradrenaline Transporter,Solute Carrier Family 6 Member 2,Neuronal NET Protein,Neurotransmitter Transporters, Noradrenaline Specific,Noradrenaline Transporter, Sodium-Dependent,Noradrenaline-Specific Neurotransmitter Transporters,Sodium Dependent Noradrenaline Transporter,Transporter Protein, Norepinephrine,Transporter, Noradrenaline,Transporter, Norepinephrine,Transporters, Noradrenaline-Specific Neurotransmitter
D057180 Frontotemporal Dementia The most common clinical form of FRONTOTEMPORAL LOBAR DEGENERATION, this dementia presents with personality and behavioral changes often associated with disinhibition, apathy, and lack of insight. DDPAC,Dementia, Frontotemporal,Dementia, Frontotemporal, with Parkinsonism,Dementia, Hereditary Dysphasic Disinhibition,Disinhibition-Dementia-Parkinsonism-Amyotrophy Complex,Disinhibition-Dementia-Parkinsonism-Amytrophy Complex,FTD-GRN,FTD-PGRN,FTDP-17,FTLD with TDP-43 Pathology,FTLD-17 GRN,FTLD-TDP,Familial Pick's Disease,Frontotemporal Dementia with Parkinsonism,Frontotemporal Dementia with Parkinsonism-17,Frontotemporal Dementia, Ubiquitin-Positive,Frontotemporal Lobar Degeneration With Ubiquitin-Positive Inclusions,Frontotemporal Lobe Dementia,Frontotemporal Lobe Dementia (FLDEM),GRN-Related Frontotemporal Dementia,HDDD1,HDDD2,Hereditary Dysphasic Disinhibition Dementia,Multiple System Tauopathy with Presenile Dementia,Semantic Dementia,Wilhelmsen-Lynch Disease,Complex, Disinhibition-Dementia-Parkinsonism-Amyotrophy,Complex, Disinhibition-Dementia-Parkinsonism-Amytrophy,Complices, Disinhibition-Dementia-Parkinsonism-Amyotrophy,Complices, Disinhibition-Dementia-Parkinsonism-Amytrophy,Dementia, Frontotemporal Lobe,Dementia, Frontotemporal Lobe (FLDEM),Dementia, GRN-Related Frontotemporal,Dementia, Semantic,Dementia, Ubiquitin-Positive Frontotemporal,Dementias, Frontotemporal,Dementias, Frontotemporal Lobe,Dementias, Frontotemporal Lobe (FLDEM),Dementias, GRN-Related Frontotemporal,Dementias, Semantic,Dementias, Ubiquitin-Positive Frontotemporal,Disease, Familial Pick's,Disease, Wilhelmsen-Lynch,Diseases, Familial Pick's,Diseases, Wilhelmsen-Lynch,Disinhibition Dementia Parkinsonism Amyotrophy Complex,Disinhibition Dementia Parkinsonism Amytrophy Complex,Disinhibition-Dementia-Parkinsonism-Amyotrophy Complices,Disinhibition-Dementia-Parkinsonism-Amytrophy Complices,FTLD with TDP 43 Pathology,Familial Pick Disease,Familial Pick's Diseases,Familial Picks Disease,Frontotemporal Dementia with Parkinsonism 17,Frontotemporal Dementia, GRN-Related,Frontotemporal Dementia, Ubiquitin Positive,Frontotemporal Dementias,Frontotemporal Dementias, GRN-Related,Frontotemporal Dementias, Ubiquitin-Positive,Frontotemporal Lobar Degeneration With Ubiquitin Positive Inclusions,Frontotemporal Lobe Dementias,Frontotemporal Lobe Dementias (FLDEM),GRN Related Frontotemporal Dementia,GRN-Related Frontotemporal Dementias,Lobe Dementia, Frontotemporal,Lobe Dementias, Frontotemporal,Pick's Disease, Familial,Pick's Diseases, Familial,Semantic Dementias,Ubiquitin-Positive Frontotemporal Dementia,Ubiquitin-Positive Frontotemporal Dementias,Wilhelmsen Lynch Disease,Wilhelmsen-Lynch Diseases

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