Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD)

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.

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.

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.

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.