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. 2023 Apr 15;44(6):2245-2253.
doi: 10.1002/hbm.26206. Epub 2023 Jan 17.

Unravelling neurotransmitters impairment in primary progressive aphasias

Enrico Premi  1 , Juergen Dukart  2   3 , Irene Mattioli  4 , Ilenia Libri  4 , Marta Pengo  5 , Yasmine Gadola  4 , Maria Cotelli  6 , Rosa Manenti  6 , Giuliano Binetti  7 , Stefano Gazzina  8 , Antonella Alberici  9 , Mauro Magoni  1 , Giacomo Koch  10   11 , Roberto Gasparotti  12 , Alessandro Padovani  4   9 , Barbara Borroni  4   9
Affiliations

Unravelling neurotransmitters impairment in primary progressive aphasias

Enrico Premi et al. Hum Brain Mapp. .

Abstract

Primary progressive aphasias (PPAs) are a group of neurodegenerative diseases mainly characterized by language impairment, and with variably presence of dysexecutive syndrome, behavioural disturbances and parkinsonism. Detailed knowledge of neurotransmitters impairment and its association with clinical features hold the potential to develop new tailored therapeutic 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 103 PPA patients and 80 age-matched healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in PPA patients (relative to HC) are correlated with specific neurotransmitter systems. As compared to HC, voxel-based brain changes in PPA were significantly associated with spatial distribution of serotonin, dopamine, and glutamatergic pathways (p < .05, False Discovery Rate corrected-corrected). Disease severity was negatively correlated with the strength of GMV colocalization of D1 receptors (p = .035) and serotonin transporter (p = .020). Moreover, we observed a significant negative correlation between positive behavioural symptoms, as measured with Frontal Behavioural Inventory, and GMV colocalization of D1 receptors (p = .007) and serotonin transporter (p < .001). This pilot study suggests that JuSpace is a helpful tool to indirectly assess neurotransmitter deficits in neurodegenerative dementias and may provide novel insight into disease mechanisms and associated clinical features.

Keywords: behavioural disturbances; magnetic resonance imaging; neurotransmitters; positron emission tomography; primary progressive aphasia.

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Conflict of interest statement

No competing interests were disclosed.

Figures

FIGURE 1
FIGURE 1
Voxel‐wise analyses in avPPA and in svPPA as compared to HC. Panel A: avPPA < HC. Panel B: svPPA < HC. Inverse comparisons (avPPA > HC and svPPA > HC) did not show any clusters above the pre‐established statistical threshold. Only clusters surviving correction for multiple comparisons (p < .05 familywise error [FEW] whole‐brain) were shown. Significant clusters were superimposed on a standardized MRI T1 3D template. avPPA, nonfluent variant of primary progressive aphasia; svPPA, semantic variant of primary progressive aphasia HC, healthy controls
FIGURE 2
FIGURE 2
Results of spatial correlation analyses for PPA patients. Fisher's Z‐transformed correlation coefficients with respective neurotransmitter maps are displayed. Error bars represent the parametric 95% confidence interval of the mean. DAT, dopamine transporter; FDOPA, FluoroDOPA; GABAa, γ‐aminobutyric acid type A; NAT, noradrenaline; SERT, serotonin transporter. Panel A: Results of spatial correlation analyses in patients with nonfluent variant of primary progressive aphasia (avPPA); Panel B: Results of spatial correlation analyses in patients with semantic variant of primary progressive aphasia (svPPA). *p‐values < .004 (corrected for multiple comparisons)
FIGURE 3
FIGURE 3
Association between disease severity and GMV‐neurotransmitter correlation coefficients. CDR SOB, CDR dementia staging instrument plus behaviour and language domains from the National Alzheimer's Coordinating Center and Frontotemporal lobar degeneration modules sum of boxes. Correlation coefficients (Fisher's Z − Spearman rho) for each neurotransmitter on y‐axis
See this image and copyright information in PMC

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