In the present work, we showed that in addition to a well-known decreased 123I-FP-CIT uptake involving the striatum, early PD subjects exhibit a significant uptake reduction in extrastriatal regions including the pallidum, amygdala and insula.
123I-FP-CIT impairment in pallidum was recently observed by Lee et al. [18]. 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 [17]. 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 vivo 11C-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. A reduced 123I-FP-CIT uptake in the amygdala was observed. These findings are 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 [19].
Our correlation analysis confirmed that motor impairment as measured by MDS-UPDRS III total score was associated with decreased putaminal 123I-FP-CIT uptake [20]. 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 [21].
Clinical correlates of 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 [22]. While a trend association was found between GDS and pallidal 123I-FP-CIT uptake, 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 [24].
Finally, a significant association was found between SCOPA-GI subscore and caudate/putamen uptake. This confirms previous observations from Hinkle et al. [25], 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. [26] 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 [27], 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.
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 3–4 h after 123I-FP CIT injection, which is the ideal timeframe for DAT evaluation, whereas the recommended time window for extrastriatal SERT is 2–3 h [2]. Nonetheless, due to a slow 123I-FP-CIT washout, we expect SERT binding to be relatively stable at 3–4 h [28].