In the present work, we showed that in addition to a well-known decrease in 123I-FP-CIT uptake involving the striatum, early PD subjects exhibit a significant uptake reduction in extrastriatal regions including the pallidum, amygdala and insula. As extrastriatal 123I-FP-CIT binding mainly derives from SERT [2], we took advantage of the same scanning session of a large PD cohort to confirm early binding changes in regions outside the striatum compared to similarly-aged Controls.
123I-FP-CIT impairment in pallidum was recently observed by Lee et al. [21]. 11C-PE2I and 11C-DASB PET studies showed that while the lateral part of the pallidum (globus pallidum externus) has a similar proportion of serotonergic and dopaminergic terminals, the medial part (globus pallidus internus) is mainly a serotonergic nucleus [20]. In addition, our PD subjects exhibited an impaired extrastriatal uptake in the insula and amygdala. These findings confirm recent data by Pilotto et al. showing decreased 123I-FP-CIT uptake in insula, thalamus and cingulate in both PD and dementia with Lewy bodies [9]. Moreover, they confirm previous neuropathological evidence and in vivo11C-DASB-PET and 123I-FP-CIT SPECT studies showing an altered serotonergic uptake for PD in the insula [6, 8], providing additional value for 123I-FP-CIT SPECT, a major diagnostic imaging tool in daily clinical practice. Findings of a reduced 123I-FP-CIT uptake in the amygdala are also in line with post-mortem studies using chromatography and enzyme-linked immunosorbent assay showing that PD subjects had reduced dopamine and noradrenaline levels in the amygdala [22].
Our correlation analysis confirmed that motor impairment as measured by MDS-UPDRS III total score was associated with decreased putaminal 123I-FP-CIT uptake [23]. It might seem surprising that MDS-UPDRS III was not more strongly correlated with striatal ROIs 123I-FP-CIT uptake. However, a recent psychometric assessment of MDS-UPDRS part II and III scales in PD subjects enrolled into the PPMI cohort showed an important floor effect, which can explain the moderate association for our cohort [24].
Clinical association with an extensive serotonergic deficit may include apathy, emotional disturbances, depression, cognitive deficits, and dysautonomic manifestations in PD, all of which being potentially present early in the disease course or even in its prodromal phase [25].
Previous studies did not show any significant correlation between striatal 123I-FP-CIT binding and non-motor symptoms such as fatigue, depression and excessive daytime sleepiness in PD [26]. Using a ROI-based approach to assess the contribution of extrastriatal ROIs, Qamhawi et al. observed a reduced 123I-FP-CIT binding in the raphe nucleus in early PD patients from the PPMI initiative compared to Controls (although only 12.5% of PD had values below 1.5 standard deviation). They also found that raphe nucleus binding was associated with rest tremor amplitude, constancy and severity, but not with non-motor symptoms such as depression, REM-sleep behaviour disorder and excessive daytime sleepiness [27].
While a trend association was found between GDS and pallidal 123I-FP-CIT uptake in the present study, we did not find a significant correlation between SERT-rich regional uptake and cognitive impairment as measured with MOCA. One reason might be that other monoaminergic pathways are involved in the pathophysiology of cognitive impairment [23] and that larger samples would be necessary to tackle such complex processes. In addition, our PD cohort mainly consisted of early subjects with relatively preserved cognition (mean MoCA 27.4), so admittedly, a significant correlation between SERT binding and depression/cognitive scales could have been observed in cohorts with a broader range of impairment [28].
Interestingly, correlations between striatal and extrastriatal regions binding among PD patients showed that caudate nucleus and putamen 123I-FP-CIT uptake impairment was associated with concomitant reductions in insula and amygdala binding in the full cohort analyses and also in the PD subgroup with GDS ≥ 5. However, when assessing these potential associations in the subgroup with mild cognitive impairment (MOCA ≤ 25, n = 30), we did not observe such correlations, except for a trend association between putamen and amygdala uptake (p=0.09). The smaller subgroup could explain the lack of significant association. In addition, changes in striatal and extrastriatal binding can be of a different magnitude in patients with cognitive impairment, although we did not find any significant relationship between extrastriatal binding and cognitive impairment.
Our early PD group did not show any major signs of excessive daytime sleepiness, with ESS scores similar to Controls (p = 0.68). At variance with Yousaf et al. [29], no significant correlation between ESS and striatal 123I-FP-CIT uptake was observed in PD (all p > 0.29). Differences in the inclusion criteria could explain the apparently opposite findings. In fact, Yousaf et al. [29] performed between-group comparisons of PD with or without excessive daytime sleepiness, whereas we assessed correlations with striatal/extrastriatal 123I-FP-CIT using a cohort with relatively low ESS score.
In contrast, we observed that PD group had a significantly increased RBDSQ score (p < 0.001) relative to Controls, with 51/154 PD (33.1%) having RBDSQ ≥ 5. Moreover, higher RBDSQ was associated with lower 123I-FP-CIT binding in caudate nucleus, putamen and pallidum (all p < 0.05). These findings are in line with Pagano et al., who showed that RBD was associated with faster striatal dopaminergic decline [30].
Finally, a significant association was found between SCOPA-GI subscore and caudate/putamen uptake. This confirms previous observations from Hinkle et al. [31], who described an association between SCOPA-GI score (especially constipation items) and both regions. Additionally, we observed that the SCOPA-URO subscore was also negatively correlated with striatal uptake. This is in line with previous findings from Kim et al. [32] who recently found a correlation between putamen uptake and SCOPA-URO subscore also including the PPMI cohort. For both studies from Hinkle and Kim, SPECT/MRI coregistration was not performed. While our findings are of interest, they should be interpreted with an important caveat in mind. In fact, while bowel motility in late-life has been associated with postmortem neuron density in the substantia nigra [33], a causal relationship between presynaptic striatal dopamine uptake and gastrointestinal impairment in early PD would be hasty. Indeed, one hypothesis would be that dysautonomia would appear concurrently to striatal dopaminergic degeneration and not necessarily be driven by it.
Studies on rats and humans have shown conflicting results regarding the effect of antidepressant medication (SSRI/SNRI) on 123I-FP-CIT uptake values. In rats, sub-chronic administration of fluvoxamine was not associated with significant changes in striatal 123I-FP-CIT uptake [34]. In humans, higher binding in striatal regions and lower binding in extrastriatal regions was observed after acute treatment of paroxetine [35], while chronic treatment was associated with lower striatal binding [36], which is in line with our findings.
The present study has several major strengths: first, it is based on a large cohort of well-characterized PD and CTL subjects who underwent extensive clinical motor and non-motor evaluation. In addition, we included subjects whose SPECT was acquired within three months of a high-resolution anatomical MRI in order to proceed to MRI/SPECT coregistration and to provide PVE-corrected results. Although our included subjects represent about half of the total PD subjects in the PPMI cohort, given the stringent inclusion criteria we applied for analyses purposes, we believe this provides a major insight into the pathophysiology of monoaminergic degeneration in PD. The present work also presents some limitations. As this is the case in similar clinical studies, diagnoses are not based on neuropathology, so we cannot exclude diagnostic misattribution, especially since some PD cases were enrolled at a very early stage (10 subjects with < 6-month disease duration). In addition, SPECT acquisition was performed 3-4h after 123I-FP CIT injection, which is the ideal timeframe for DAT evaluation, whereas the recommended time window for extrastriatal SERT is 2-3h [2]. Nonetheless, due to a slow 123I-FP-CIT washout, we expect SERT binding to be relatively stable at 3-4h [37].