Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study.

Humans Frontotemporal Dementia / diagnostic imaging C9orf72 Protein / genetics Acetylcholine Dopamine Serotonin Mutation Pick Disease of the Brain Magnetic Resonance Imaging / methods tau Proteins / genetics

Frontotemporal dementia Frontotemporal lobar degeneration Genes Magnetic resonance imaging Mutation Neurotransmitters Positron emission tomography

Journal

Neurobiology of disease

ISSN: 1095-953X

Titre abrégé: Neurobiol Dis

Pays: United States

ID NLM: 9500169

Informations de publication

Date de publication:
04 2023

Historique:

received: 05 02 2023

revised: 01 03 2023

accepted: 04 03 2023

pubmed: 11 3 2023

medline: 23 3 2023

entrez: 10 3 2023

Statut: ppublish

Résumé

Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p < 0.05, Family Wise Error corrected). In symptomatic FTD, a widespread involvement of dopamine, serotonin, glutamate and acetylcholine pathways across all genetic subtypes was found. Social cognition scores, loss of empathy and poor response to emotional cues were found to correlate with the strength of GMV colocalization of dopamine and serotonin pathways (all p < 0.01). This study, indirectly assessing neurotransmitter deficits in monogenic FTD, provides novel insight into disease mechanisms and might suggest potential therapeutic targets to counteract disease-related symptoms.

Sections du résumé

BACKGROUND

METHODS

In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD.

RESULTS

In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p < 0.05, Family Wise Error corrected). In symptomatic FTD, a widespread involvement of dopamine, serotonin, glutamate and acetylcholine pathways across all genetic subtypes was found. Social cognition scores, loss of empathy and poor response to emotional cues were found to correlate with the strength of GMV colocalization of dopamine and serotonin pathways (all p < 0.01).

CONCLUSIONS

This study, indirectly assessing neurotransmitter deficits in monogenic FTD, provides novel insight into disease mechanisms and might suggest potential therapeutic targets to counteract disease-related symptoms.

Identifiants

DOI: 10.1016/j.nbd.2023.106068 PMID: 36898614

pubmed: 36898614

pii: S0969-9961(23)00082-7

doi: 10.1016/j.nbd.2023.106068

pii:

doi:

Substances chimiques

C9orf72 Protein 0

Acetylcholine N9YNS0M02X

Dopamine VTD58H1Z2X

Serotonin 333DO1RDJY

tau Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng