Parkinson’s disease laterality: a ¹¹C-PE2I PET imaging study

Asymmetry of striatal dopaminergic deficits and subsequent lateralisation of motor symptoms are key features of idiopathic Parkinson's disease (PD) [1] and as such are considered supporting factors during the diagnostic process [2]. Remarkably, after decades of research, the underlying causes of PD asymmetry remain poorly understood. Some consider it coincidental, while others have drawn links to handedness, certain genetic loci and environmental factors [3‐6].

Asymmetry of motor symptoms has been shown to correspond to asymmetry of striatal dopaminergic deficits in early PD [7, 8]. PET studies show that the degree of asymmetry in striatal dopamine transporter (DAT) tracer binding becomes less prominent over the course of the disease [7, 9]. However, clinical studies indicate that the motor symptoms retain asymmetry over many years [10, 11].

To our knowledge, there are currently no longitudinal studies evaluating the progression of asymmetry in clinical symptoms and dopaminergic integrity in moderate PD. To address this, we performed serial clinical ratings and dopaminergic brain imaging over a 19-month period. To evaluate dopaminergic terminal integrity, we use ¹¹C-PE2I [¹¹C N-(3-iodopro-2E-enyl)-2β-carbomethoxy-3β-(4ʹ-methylphenyl) nortropane] PET, which has been shown to have high specificity for the dopamine transporter (DAT) [12]. To monitor clinical progression, we use the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) [13].

Based on previous reports [7, 10, 11, 14], we hypothesise that in moderate PD, the decline of striatal DAT density in the ipsilateral side is greater than in the contralateral side, and that the asymmetry of striatal DAT degeneration becomes less marked over 19 months. We expect the progress of clinical scores to occur in a similar pattern between the clinically most and least affected body sides.

In this study, we assessed striatal dopaminergic decline and motor symptom progression in moderate PD over 19 months. We found that the effect of time on striatal ¹¹C-PE2I BP_ND values was more pronounced in the ipsilateral as compared to the contralateral side. However, our data showed no differential effect of time on MDS-UPDRS-III scores between the clinically most and least affected body sides.

Most imaging studies on PD progression have approached striatal DAT degeneration without taking into account PD-related asymmetry [24]. To our knowledge, there have been only two longitudinal imaging studies in the literature that discuss PD asymmetry with respect to striatal imaging data [7, 9]. Nandhagopal and colleagues [7] proposed that the rate of dopaminergic decline is faster in the ipsilateral than in the contralateral striatum, especially in early and moderate stages of PD. However, the integrity of dopaminergic terminals was evaluated using ¹¹C-methylphenidate, which may yield biased values depending on the severity of dopaminergic denervation [25]. Simuni and colleagues [9] noted that in the early stages of PD, changes in DAT binding in the ipsilateral putamen were more pronounced as compared to reductions seen in the contralateral putamen after a 5-year follow-up period. Nevertheless, in the latter report, the authors showed data only for the contralateral putamen, excluding useful information from the other striatal ROIs [9].

With respect to motor symptoms, a number of studies evaluating PD patients over a wide range of disease durations demonstrate retention of asymmetry over many years [10, 11]. However, two interesting studies [26, 27] using multiple regression analyses and focussing on the earlier stages of PD showed that shorter disease duration and younger age at onset correlate with higher motor symptom asymmetry. These results suggest that the progression of motor severity might not be similar across sides at the initial stages of the disease.

Our data demonstrate that the asymmetry of motor symptoms remains over 19 months in moderate PD. In contrast, a significant time-side interaction for ¹¹C-PE2I demonstrates that striatal DAT asymmetry becomes less prominent over the same period. That we found significant inverse relationships between striatal DAT density and motor severity at baseline, and negative correlations between changes in ¹¹C-PE2I BP_ND values and corresponding changes in motor scores, support the validity of this biomarker for tracking progression in moderate-stage PD. The mismatch of asymmetry trends between clinical and PET imaging data, and the failure to find a significant correlation between DAT density and corresponding motor scores at the follow-up time point, however, suggests differential patterns of progression for each aspect of the disease. Previous work describes three distinct phases of motor progression [28‐30]; there is a significant improvement in motor scores attributed to treatment effects during the first two years following diagnosis, then motor scores remain relatively stable for a number of years from early to moderate PD, followed by a significant worsening of motor function in the moderate/advanced stages [28‐30]. In contrast, the progressive decline in DAT density has been characterised as following an exponential decay function [31, 32]. Previous multi-tracer PET studies show that in the early stages of PD, dopaminergic compensatory adjustments, namely downregulation of DAT and upregulation of aromatic amino acid decarboxylase (AADC), are more prominent in the contralateral as compared to the ipsilateral striatum [31, 32]. However, as the disease progresses, these asymmetric compensatory responses are observed to decline [31]. Thus, the convergence of DAT density between the sides observed in the current report may be explained by a ‘floor effect’ limiting the continual reductions of the contralateral striatum in moderate PD. The exact mechanisms underlying the non-linear pattern in longitudinal compensatory evolution are unclear, but might be related to progressive and abnormal protein accumulation of α-synuclein [33] and/or chronic use of anti-parkinsonian medication [34]. Our results are in line with previous evidence, demonstrating that the development of each disease characteristic progresses according to different patterns. Aside from the degeneration of dopamine transporters, there are likely multiple other factors contributing to the pattern of motor progression, including functional changes within and beyond the dopaminergic system. Identification of novel factors for improved prediction of motor progression including those related to age, sex, baseline motor scores, cognitive function, clinical subtypes, imaging tracer (pre-and post-synaptic dopaminergic markers) and CSF biomarkers (α-synuclein, β-amyloid, and tau) is warranted.

We did not calculate an average rate of change for BP_ND values and MDS-UPDRS-III scores, as we do not assume a linear progression model of DAT decline in the course of PD [35]. We do not believe that aging can explain the current results as previous work demonstrates that age-related physiological decline occurs symmetrically [36]. The duration of the follow-up period (19 months) may be viewed as a methodological limitation. Although it would be ideal to continue with a third follow-up scan and/or include longer intervals between visits, we believe that the 19-month period was sufficient to reveal the change in BP_ND values and MDS-UPDRS-III scores in this cohort for the aims of the current study [12]. We believe that a larger number of participants would add validity to the robustness of our results. Nevertheless, we acknowledge the limitations that relate to feasibility issues, specific to the study population and the risks associated with exposure to additional ionising radiation.

We propose that while asymmetry in both striatal dopaminergic degeneration and motor symptoms continues to occur in moderate PD, its magnitude may change over the course of the disease.