Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD)
- 1Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin, Dublin, Ireland
- 2Department of Neurology, St James’s Hospital, Dublin, Ireland
- 3The Irish FTD/FTLD Network, Dublin, Ireland
Abstract
Background: Frontotemporal dementia syndromes encompass a genetically, clinically and radiologically heterogeneous set of conditions with distinctive clinical and imaging characteristics. The main FTD phenotypes exhibit strikingly different disease burden patterns with a predilection to specific brain regions and relative sparing of others. The apparent selectivity of cerebral involvement in FTD has not been fully elucidated.
Methods: A prospective neuroimaging study has been undertaken with a uniform imaging protocol to characterise atrophy patterns in ALS-FTD, behavioural variant FTD, nonfluent variant primary progressive aphasia, and semantic variant primary progressive aphasia and evaluate associations with physiological neurotransmitter receptor expression maps. Anatomical correlations between focal volume loss and a large panel of neurotransmitters were systematically evaluated and associations ranked.
Results: Associations were noted with GABAergic, opioid, cannabinoid, microglial and acetylcholine systems in ALSFTD-C9NEG. Correlations were observed with opioid, glutaminergic, and synaptic vesicle glycoprotein 2A receptor populations in ALSFTD-C9POS. Atrophy in bvFTD showed predilection to serotonergic, glutaminergic, opioid, GABAergic and cannabinoid circuits. Volume loss in nfvPPA colocalised with GABAergic, opioid, microglial, serotonergic, cannabinoid, acetylcholine, glutaminergic and dopaminergic networks. A multitude of neurotransmitter populations are implicated in svPPA including opioid, serotonergic, GABAergic, dopaminergic, and microglial systems.
Discussion: The distinctive neuroimaging signatures of FTD phenotypes exhibit spatial associations with physiological neurotransmitter receptor density maps. The propensity of atrophy to specific brain regions in FTD subtypes may be defined by neurotransmitter populations. Our findings indirectly support the notion of neurotransmitter-system defined connectivity-based disease propagation in FTD.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00415-026-14216-y.
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BibTeX
@article{tahedl2026neurotransmitterdefined,
title = {{Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD)}},
author = {Marlene Tahedl and Alison Toomey and Naser Mandal and Sarah Mangan and We Fong Siah and Ee Ling Tan and Orla Hardiman and Jana Kleinerova and Mary Clare McKenna and Siobhan Hutchinson and Jasmin Lope and Peter Bede},
journal = {Journal of Neurology},
year = {2026},
month = oct,
doi = {10.1007/s00415-026-14216-y},
url = {https://doi.org/10.1007/s00415-026-14216-y},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD)
AU - Marlene Tahedl
AU - Alison Toomey
AU - Naser Mandal
AU - Sarah Mangan
AU - We Fong Siah
AU - Ee Ling Tan
AU - Orla Hardiman
AU - Jana Kleinerova
AU - Mary Clare McKenna
AU - Siobhan Hutchinson
AU - Jasmin Lope
AU - Peter Bede
PY - 2026
DA - 2026/10/21
JO - Journal of Neurology
DO - 10.1007/s00415-026-14216-y
UR - https://doi.org/10.1007/s00415-026-14216-y
AB - Background: Frontotemporal dementia syndromes encompass a genetically, clinically and radiologically heterogeneous set of conditions with distinctive clinical and imaging characteristics. The main FTD phenotypes exhibit strikingly different disease burden patterns with a predilection to specific brain regions and relative sparing of others. The apparent selectivity of cerebral involvement in FTD has not been fully elucidated. Methods: A prospective neuroimaging study has been undertaken with a uniform imaging protocol to characterise atrophy patterns in ALS-FTD, behavioural variant FTD, nonfluent variant primary progressive aphasia, and semantic variant primary progressive aphasia and evaluate associations with physiological neurotransmitter receptor expression maps. Anatomical correlations between focal volume loss and a large panel of neurotransmitters were systematically evaluated and associations ranked. Results: Associations were noted with GABAergic, opioid, cannabinoid, microglial and acetylcholine systems in ALSFTD-C9NEG. Correlations were observed with opioid, glutaminergic, and synaptic vesicle glycoprotein 2A receptor populations in ALSFTD-C9POS. Atrophy in bvFTD showed predilection to serotonergic, glutaminergic, opioid, GABAergic and cannabinoid circuits. Volume loss in nfvPPA colocalised with GABAergic, opioid, microglial, serotonergic, cannabinoid, acetylcholine, glutaminergic and dopaminergic networks. A multitude of neurotransmitter populations are implicated in svPPA including opioid, serotonergic, GABAergic, dopaminergic, and microglial systems. Discussion: The distinctive neuroimaging signatures of FTD phenotypes exhibit spatial associations with physiological neurotransmitter receptor density maps. The propensity of atrophy to specific brain regions in FTD subtypes may be defined by neurotransmitter populations. Our findings indirectly support the notion of neurotransmitter-system defined connectivity-based disease propagation in FTD. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00415-026-14216-y.
SN - 0340-5354
SN - 1432-1459
ER -