Investigation of serotonergic Parkinson's disease-related covariance pattern using [11C]-DASB/PET

Abstract

We used positron emission tomography imaging with [¹¹C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)- benzonitrile (DASB) and principal component analysis to investigate whether a specific Parkinson's disease (PD)-related spatial covariance pattern could be identified for the serotonergic system. We also explored if non-manifesting leucine-rich repeat kinase 2 (LRRK2) mutation carriers, with normal striatal dopaminergic innervation as measured with [¹¹C]-dihydrotetrabenazine (DTBZ), exhibit a distinct spatial covariance pattern compared to healthy controls and subjects with manifest PD. 15 subjects with sporadic PD, eight subjects with LRRK2 mutation-associated PD, nine LRRK2 non-manifesting mutation carriers, and nine healthy controls participated in the study. The analysis was applied to the DASB non-displaceable binding potential values evaluated in 42 pre-defined regions of interest. PD was found to be associated with a specific spatial covariance pattern, comprising relatively decreased DASB binding in the caudate, putamen and substantia nigra and relatively preserved binding in the hypothalamus and hippocampus; the expression of this pattern in PD subjects was significantly higher than in healthy controls (P < 0.001) and correlated significantly with disease duration (P < 0.01) and with DTBZ binding in the more affected putamen (P < 0.01). The LRRK2 non-manifesting mutation carriers expressed a different pattern, also significantly different from healthy controls (P < 0.001), comprising relatively decreased DASB binding in the pons, pedunculopontine nucleus, thalamus and rostral raphe nucleus, and with relatively preserved binding in the hypothalamus, amygdala, hippocampus and substantia nigra. This pattern was not present in either sporadic or LRRK2 mutation-associated PD subjects. These findings, although obtained with a relatively limited number of subjects, suggest that specific and overall distinct spatial serotonergic patterns may be associated with PD and LRRK2 mutations. Alterations in regions where relative upregulation is observed in both patterns may be indicative of compensatory mechanisms preceding or protecting from disease manifestation.

Fig. 1

Serotonergic Parkinson's disease-related pattern (SPDRP) identified by comparing sporadic Parkinson's disease subjects and healthy controls. Regions with significant weights on the averaged SPDRP were overlaid onto a T1 MRI image. Blue (red) indicates regions with relatively decreased (increased) binding in sporadic Parkinson's disease subjects compared to healthy controls. MRI = magnetic resonance imaging.

Fig. 2

Subject scores projected onto the serotonergic Parkinson's disease-related pattern (SPDPR) for all four subject groups. The three outliers were labeled as H1013 and H1079 in the LRRK2-PD group, and H814 in the LRRK2-NMC group. sPD = sporadic Parkinson's disease subjects; LRRK2-PD = manifested LRRK2 mutation carriers; LRRK2-NMC = non-manifesting LRRK2 mutation carriers; * = significant at P < 0.05 level; ** = significant at P < 0.01 level.

Fig. 3

Scatter plot of projected subject scores, denoting the strength of the serotonergic Parkinson's disease-related pattern (SPDRP) expression as a function of disease durations (left) and as a function of DTBZ binding expressed as fractions to age-matched normal controls (right) for sporadic PD and LRRK2-PD. The two outliers are labeled in the same way as in Fig.2. The best line fit was done without these two subjects. PD = Parkinson's disease; LRRK2-PD = manifest LRRK2 mutation carriers.

Fig. 4

Subject scores projected onto LRRK2-NMC pattern in all four subject groups. sPD = sporadic Parkinson's disease subjects; LRRK2-PD = manifested LRRK2 mutation carriers; LRRK2-NMC = non = manifesting LRRK2 mutation carriers; ** = significant at P < 0.01 level.

Fig. 5

Serotonergic LRRK2-NMC pattern identified by comparing LRRK2-NMC and healthy controls. Regions with significant weights on the averaged LRRK2-NMC pattern were overlaid onto a T1 MRI image. Blue (red) indicates regions with relatively decreased (increased) binding in LRRK2-NMC compared to healthy controls. LRRK2-NMC = non-manifesting LRRK2 mutation carriers; MRI = magnetic resonance imaging; PPN = pedunculopontine nucleus.