Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems
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eLife assessment
This study presents important findings linking structural and functional changes in frontotemporal dementia to underlying neurotransmitter systems. The evidence to support the claims is solid, however, relationships are relatively modest and there are limitations regarding the neurotransmitter data. This study will appeal to clinicians and neuroscientists who are interested in the potential effects of certain neurotransmitter systems on clinical features of frontotemporal dementia.
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Abstract
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).
Article activity feed
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eLife assessment
This study presents important findings linking structural and functional changes in frontotemporal dementia to underlying neurotransmitter systems. The evidence to support the claims is solid, however, relationships are relatively modest and there are limitations regarding the neurotransmitter data. This study will appeal to clinicians and neuroscientists who are interested in the potential effects of certain neurotransmitter systems on clinical features of frontotemporal dementia.
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Reviewer #1 (Public Review):
In "Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems" by Hahn et al, the authors investigate the association between structural and functional alterations in bvFTD and neurotransmitter systems. The authors take this a step further and also relate functional activation reductions in bvFTD to mRNA expression levels of neurotransmitter systems, and clinical/behavioural measures of the bvFTD subjects. The authors find significant associations between fALFF bvFTD maps and serotonin, dopamine, noradrenaline, and GABAa receptors/transporters, demonstrating a link between specific neurotransmitter systems and functional alterations in bvFTD. They successfully achieve their aim of finding neurotransmitter systems …
Reviewer #1 (Public Review):
In "Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems" by Hahn et al, the authors investigate the association between structural and functional alterations in bvFTD and neurotransmitter systems. The authors take this a step further and also relate functional activation reductions in bvFTD to mRNA expression levels of neurotransmitter systems, and clinical/behavioural measures of the bvFTD subjects. The authors find significant associations between fALFF bvFTD maps and serotonin, dopamine, noradrenaline, and GABAa receptors/transporters, demonstrating a link between specific neurotransmitter systems and functional alterations in bvFTD. They successfully achieve their aim of finding neurotransmitter systems that may subserve functional changes in bvFTD. This is strengthened by the finding that receptor-fALFF correspondence is correlated with performance on cognitive tests across individuals. This multimodal approach is important for informing clinical interventions in bvFTD and the authors nicely demonstrate a link between functional changes in bvFTD, receptor systems, and cognition. In my opinion, the primary weakness of the study is that the effects are small, although I wonder whether this is related to the fact that some of the neurotransmitter receptor maps have small sample size and low sensitivity in the cortex.
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Reviewer #2 (Public Review):
The aim of this study was to relate functional alterations in patients with bvFTD to neurotransmitter maps provided by the JuSpace toolbox in order to better understand the underlying pathological mechanisms of this disease.
A strength of the study is the novelty of this aim. Some weaknesses are the different fMRI parameters of patients belonging to each centre and a better explanation of some methodological choices as well a better description of the JuSpace toolbox.
The authors have achieved their aims and the results seem to support some conclusions, although the results should be interpreted in light of a potential lack of proper control for multiple comparisons.
This work will increase the use of approaches that relate brain abnormalities to neurotransmitters and transcriptomics.
There is an increasing …
Reviewer #2 (Public Review):
The aim of this study was to relate functional alterations in patients with bvFTD to neurotransmitter maps provided by the JuSpace toolbox in order to better understand the underlying pathological mechanisms of this disease.
A strength of the study is the novelty of this aim. Some weaknesses are the different fMRI parameters of patients belonging to each centre and a better explanation of some methodological choices as well a better description of the JuSpace toolbox.
The authors have achieved their aims and the results seem to support some conclusions, although the results should be interpreted in light of a potential lack of proper control for multiple comparisons.
This work will increase the use of approaches that relate brain abnormalities to neurotransmitters and transcriptomics.
There is an increasing trend to assess the correspondence between neuroimaging alterations and detailed information of neurotransmitters across the brain. This work represents this trend and adds to an increasing body of work doing the same with transcriptomics.
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Reviewer #3 (Public Review):
This manuscript analyzed resting state functional MRI metrics related to behavioral variant frontotemporal dementia (bvFTD) for associations with patterns of neurotransmitter system receptor distribution, patterns of neurotransmitter-related gene expression, and profiles of performance on neuropsychological test battery items.
The overarching goal of the work was to assess whether these analyses point to selective vulnerability of some neurotransmitter systems in the symptomatology of bvFTD. The manuscript reports that reductions in fMRI measures of local brain functional activity in bvFTD followed the distribution of specific neurotransmitter systems. No similar findings were identified for MRI-based gray matter volume measurements.
Strengths of the manuscript include its leveraging of publicly available …
Reviewer #3 (Public Review):
This manuscript analyzed resting state functional MRI metrics related to behavioral variant frontotemporal dementia (bvFTD) for associations with patterns of neurotransmitter system receptor distribution, patterns of neurotransmitter-related gene expression, and profiles of performance on neuropsychological test battery items.
The overarching goal of the work was to assess whether these analyses point to selective vulnerability of some neurotransmitter systems in the symptomatology of bvFTD. The manuscript reports that reductions in fMRI measures of local brain functional activity in bvFTD followed the distribution of specific neurotransmitter systems. No similar findings were identified for MRI-based gray matter volume measurements.
Strengths of the manuscript include its leveraging of publicly available tools for large-scale regional brain mRNA profiles and neurotransmitter receptor distributions. An additional positive step for the literature involves further development of the concept that biomarkers of disruptions to specific functionally-connected networks may guide specific treatment strategies (as a corollary to this work, related to neurotransmitter system disruption) in neurodegenerative disease.
A weakness of the manuscript is that it is not able to directly address the main literature gap described in the Introduction -- namely, whether there is specific vulnerability of certain neuronal types versus other in bvFTD, or whether broader network/region-based neurodegeneration is the driver (and happens to include some selective neurotransmitter-related disruptions). In other words, if "A" is a biomarker of bvFTD, "A" has a partial correlation with "B", and the "AB" correlation has a partial correlation with "C", it seems too far a leap to conclude that "B" (in this case, profiles/distributions of neurotransmitter systems) is the central figure in the cascade.
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