Dopamine transporter imaging predicts clinically‐defined α‐synucleinopathy in REM sleep behavior disorder

Introduction

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia defined by dream enactment behavior and the absence of atonia during REM sleep. Individuals with idiopathic RBD (iRBD), that is, in the absence of diagnosed neurologic disorder or other etiologies, are at high risk of developing α‐synuclein‐mediated neurodegenerative Parkinsonian disorders, or α‐synucleinopathies (aSN), namely Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). ¹ , ² These disorders carry significant burden on patients, families, and the economy, and their prevalence is increasing worldwide. ³ It is therefore desirable to delay or halt the neurodegenerative process in the at‐risk population.

Individuals with iRBD could serve as a key population for clinical trials to prevent or delay aSN. While up to 90% of individuals with iRBD will go on to develop such a disorder within 15 years from RBD diagnosis, ² time to diagnosis of an aSN is variable and may occur years to even decades after the onset of RBD symptomatology. In a large multicenter study of iRBD, rate of diagnosis of an aSN was approximately 6%/year. ¹ A crucial strategy to design feasible clinical trials in the iRBD population would be to enrich the sample for increased short‐term risk of a clinically definable aSN diagnosis. Despite extensive progress in characterizing prodromal features of aSN in iRBD, clinical‐trial‐ready biomarkers that will help identify such individuals are lacking. Abnormal dopaminergic transporter (DAT) imaging has emerged as a strong candidate for predicting aSN diagnosis in iRBD, ⁴ but it is unclear whether the extent of loss of DAT density is related to the risk of aSN diagnosis.

The Parkinson’s Progression Markers Initiative (PPMI) study recruited an international, multicenter iRBD cohort enriched with abnormal DAT binding. The objectives of this analysis were to (1) examine differences in the iRBD cohort compared to PD and healthy controls (HC) in PPMI, (2) define the rate of diagnosis of a clinically‐defined aSN in this research setting, and (3) identify a quantitative measure of DAT imaging that accurately predicts prospective diagnosis of a clinically‐defined aSN in iRBD.

Methods

Data used for this analysis came from PPMI, a longitudinal, observational, international, multicenter biomarker study. Study design and methodology have been previously published ⁵ , ⁶ and are available at ppmi‐info.org.

Results

Thirty‐eight individuals with iRBD are included in this analysis, and compared with a group of 205 individuals with early untreated PD and 92 HCs with similar sex‐specific age ranges.

At baseline, the iRBD cohort had a mean age of 69.5 (SD 5.5) years, and 84% were male (Table 1). The % age/sex‐expected lowest putamen SBR, MDS‐UPDRS total score, and parts II and III subscores were higher compared to the HC but lower than the PD group. SCOPA‐AUT was higher in the iRBD cohort compared to the PD and HC groups, and olfactory function was lower in the iRBD group compared to the HC. The iRBD group had higher GDS‐15 scores and lower MoCA scores than the HC group. A greater proportion of the iRBD group had abnormal cognitive testing compared to both the HC and PD groups. Eighty‐seven percent of iRBD participants met MDS criteria for prodromal PD. Median CSF amyloid‐β _1–42 was lower in the iRBD group compared to the HC group; other CSF biomarkers did not differ between the groups including total α‐synuclein levels.

In the iRBD cohort, mean estimated duration of RBD symptoms at enrollment was 10.1 (SD 7.4; range 0.4–30.4) years. Mean duration of follow‐up from study enrollment was 4.7 (SD 0.8; range 2.2–6.2) years; 92% of the iRBD cohort were assessed at the year‐4 annual visit. Fourteen individuals (36.8%) received a research diagnosis of aSN during follow‐up; final diagnosis was PD in nine, DLB in three, and MSA in two. Median time to diagnosis was 2.5 (range 0.2–5.0) years from enrollment.

Baseline predictors of aSN diagnosis are shown in Table 2. The strongest clinical predictors of an incident aSN diagnosis were olfaction in ≤ 5th percentile for age and sex (HR = 7.35, 95%CI: 1.63–33.1; P = 0.00093), orthostatic hypotension (HR = 3.22, 95%CI: 1.10–9.43; P = 0.0333), and higher MDS‐UPDRS part III scores (HR = 1.18, 95%CI: 1.03, 1.36; P = 0.0152).

As for DAT SBR as a predictor of incident aSN diagnosis, mean %‐expected DAT SBR for age and sex in the lowest putamen was associated with increased hazards of aSN diagnosis (HR = 2.53, 95%CI 1.58, 4.06, P = 00001). In ROC analyses, 48% was identified as the cutoff for percent age/sex‐expected lowest putamen SBR that best discriminated between those who were diagnosed with an aSN versus those who were not (Fig. 1). At baseline, 12 of 14 iRBD participants diagnosed with an aSN were below this cutoff (sensitivity: 86%), whereas 20 of 24 not diagnosed were above this cutoff (specificity: 83%). Time to diagnosis was significantly shorter in those who had DAT binding below this cutoff versus those who did not (Fig. 2). Lowest putamen DAT SBR ≤ 48% of that expected for age and sex  was the strongest predictor of diagnosis of an aSN diagnosis (hazard ratio = 17.8 [95% CI: 3.79–83.3], P = 0.0003; Table 2).

In iRBD participants diagnosed with aSN, motor abnormalities as measured with the MDS‐UPRDS III increased and approached those of the PD group within 2 years of diagnosis (Fig. 3). In contrast, MDS‐UPDRS III values among iRBD participants without an aSN diagnosis remained similar to the HC group. We also explored the change in DAT SBR in those who were and were not diagnosed with aSN (Fig. 4). In the first 2 years of study enrollment, mean striatal DAT binding decreased significantly more in those who were diagnosed versus those who were not (mean percent decrease 19.6 vs. 5.8; P = 0.0061). In comparison, mean striatal DAT SBR in the PD group decreased over 2 years by an average of 17.5%.

Discussion

We demonstrate the utility of DAT SBR to accurately identify individuals at short‐term risk of being diagnosed with a clinically‐defined aSN in a multicenter cohort of individuals with iRBD. We show that the extent of DAT SBR has a strong relationship with the risk of and time to diagnosis. In this cohort enriched for abnormal DAT binding, 37% of the cohort received an aSN diagnosis during an average follow‐up of 4 years. The rate of diagnosis was 9%/year, in contrast to 6%/year in other iRBD cohorts that were not enriched for abnormal DAT binding. ¹

While the majority of individuals with IRBD will go on to develop a clinically‐defined aSN, ² this may occur only several years, or even decades, after the onset of RBD symptomatology. ² , ²¹ Idiopathic RBD could serve as a key population to assess individuals prior to the onset of aSN diagnosis and therefore to enable clinical trials to prevent disability from aSN. However, for such clinical trials to be feasible, it must be possible to accurately identify a group of iRBD patients near to diagnosis. DAT imaging has emerged as a biomarker predictive of PD risk among individuals with iRBD ²² as well as other at‐risk groups including those with olfactory loss ²³ and genetic mutations. ²⁴ We have herein demonstrated the utility of quantitative measures of DAT binding, namely DAT SBR, to predict future short‐term risk of clinically‐defined aSN diagnosis.

Individuals with iRBD who had putamen DAT binding ≤ 48% of that expected for age and sex received a research diagnosis of an aSN significantly earlier than those who did not. In addition, of those who went on to receive a diagnosis of an aSN, 86% had putamen DAT binding ≤ 48% of that expected for age and sex at baseline. Reduced DAT SBR reflects loss of substantia nigra dopaminergic neurons. ²⁵ Available evidence based on neuropathological and imaging studies indicates that this neuronal loss begins years before motor manifestations of PD are fully manifest. ²⁶

As in other studies, ¹ , ²³ , ²⁷ , ²⁸ olfactory dysfunction was greater in those who received an aSN diagnosis, and orthostatic hypotension more prevalent. These features are consistent with the Braak hypothesis for progression of PD neuropathology, ²⁹ with olfactory bulb, basal forebrain, and lower brainstem regions that mediate olfaction and autonomic function being involved as the pathology reaches more rostral regions that mediate RBD. ³⁰ However, olfactory loss, orthostatic hypotension, and even mild motor abnormalities are nonspecific and may be seen with aging and several other neurologic and non‐neurologic disorders. In addition, a larger proportion of those diagnosed were female, but the small number of females in the cohort make conclusions about this uncertain.

In the largest prospective study of iRBD, ¹ significant predictors of diagnosis of an aSN included age, motor signs and symptoms, olfactory deficit, mild cognitive impairment, erectile dysfunction, degree of muscle activity during REM sleep, and abnormal DAT imaging. Despite the large sample size, the effect sizes were low, ranging from hazard ratios of 1.54 to 3.16. In that study, DAT imaging was only performed in a subset of participants, and standardized methods for imaging were not used across sites. Therefore, the substantially smaller effect size for DAT imaging as a predictive marker in that study is an underestimate. As for the small effect sizes for the clinically assessed markers, this further reflects that many prodromal features are nonspecific, and highlights the need for more objective quantitative measures for predicting the diagnosis of aSN in at‐risk groups. In contrast, in our cohort, the hazards of aSN diagnosis were 18 times greater in those who had abnormal DAT binding (accounting for the effects of age and sex). DAT binding is specific to nigrostriatal denervation, especially when other etiologies of reduced DAT binding, such as medications, are systematically excluded, as per the PPMI protocol. Our data are further evidence that individuals with iRBD and abnormal DAT binding constitute a key population in which to institute therapeutic trials to prevent disability from aSN. iRBD individuals with DAT SBR deficit likely have neurodegenerative neuropathological changes of aSN but without the extent of neuronal loss that reaches threshold for a clinical diagnosis.

Consistent with idea that iRBD is a prodromal manifestation of aSN, ¹ , ² several nonmotor and motor features of PD were present in our iRBD cohort, including olfactory loss, autonomic dysfunction, and neuropsychological abnormalities. Many of these motor and nonmotor measures were intermediate in range between HCs and a group of early, de novo untreated PD. A greater proportion of the iRBD group showed abnormal neuropsychological tests compared to the HC group. Cognitive dysfunction is seen in other PD at‐risk groups with abnormal DAT binding, such as older adults with hyposmia, ³¹ , ³² and cognitive abnormalities constitute one of the criteria for prodromal PD. ¹⁵ As for the greater proportion in the iRBD group demonstrating abnormal cognition compared to the PD group, while this may reflect the older age of the iRBD group, or the cognitive changes seen in prodromal/early PD, ³¹ , ³² it may also indicate the increased risk of DLB in individuals with iRBD. Indeed, RBD constitutes a core diagnostic criterion for DLB, ³³ and about half of individuals with RBD go onto to manifest the parkinsonism‐dementia syndrome ¹ of DLB. ² , ³⁴ DLB constituted 20% of cases of diagnoses in our cohort, and additional cases of Lewy body dementia may emerge with longer follow‐up. Lower CSF amyloid‐β _1–42 in our iRBD group compared to the HC group may reflect the increased risk of Alzheimer’s disease co‐pathology in aSN. ³⁵ Regarding other CSF biomarkers, the lack of substantial differences in CSF total α‐synuclein between the iRBD group and the HC group highlights the ongoing need for more accurate CSF biomarkers in PD including assays specific to pathologic forms of α‐synuclein. As for the pattern of striatal denervation indicated by the DAT binding measures, it was similar to that seen in PD ³⁶ , ³⁷ : DAT binding in putamen < caudate, with bilateral involvement but mild asymmetry, though less severe as compared to the PD group. Similarly, clinical abnormalities at baseline were less severe than in the PD group as well. Importantly, motor abnormalities increased in the RBD group who were diagnosed with an aSN and approached values seen in the PD group at about 2 years postdiagnosis. The clinical and imaging characteristics of our iRBD cohort indicate that the strategy of recruiting iRBD cohorts enriched with abnormal DAT imaging identifies individuals with measurable abnormalities that are, for the most part, not as severe as those seen in early, de novo PD (with the exception of cognitive and autonomic dysfunction), suggesting that putative preventive therapies could be especially meaningful in this population.

Short‐term changes in DAT binding have the potential to identify longer‐term outcomes in early PD. ³⁸ Iranzo et al. ³⁹ reported a significant reduction in DAT binding in iRBD over a 3‐year follow‐up period, which was greater in those who went on to be diagnosed with an aSN compared to those who were not. Similarly, among our sample which was enriched for abnormal DAT binding, there was a significant decrease in DAT SBR over a 2‐year period, with declines being greater among those who were diagnosed with aSN compared to those who were not. There are preliminary data to indicate that DAT SBR also significantly declines in other groups at risk for aSN, such as carriers of mutations associated with PD risk. ²⁴ These data provide preliminary evidence that DAT SBR may be useful not only as an enrichment biomarker in clinical trials but also potentially as an outcome measure to monitor disease (nigrostriatal deficit) progression over time even during the period prior to aSN diagnosis.

In other iRBD cohorts, ¹ , ² approximately 30–50% of those who develop a clinically‐defined disorder have a motor‐predominant clinical syndrome and 30–50% have a cognitive syndrome. In our cohort, the site investigator indicated PD as the research diagnosis in approximately 80% of participants. This difference in profile of the clinical syndrome emerging in our iRBD cohort could be the result of enrichment of our cohort with abnormal DAT binding, and again reflects the potential utility of DAT imaging for sample selection in PD‐prevention trials. Future studies will be needed to determine if enrichment based on other criteria, including cognitive function, will modify the clinical features and diagnoses that emerge on follow‐up.

Limitations of this study include the small sample size of the iRBD group that likely reduced that reliability of the effect sizes demonstrated. Due to the small sample size, we were not able to examine potential confounders in the relationship between DAT SBR and aSN risk in multivariable analysis. The cutoff of DAT SBR for age and sex must be replicated in independent studies and on larger cohorts and should be considered an estimate. In addition, our study included only a small number of individuals with iRBD with normal DAT SBR. Thus, our results may not apply to the general iRBD population. Importantly, it is possible that it is those individuals who will ultimately benefit most from disease‐prevention strategies. Finally, the PPMI sample, in general, is largely white and non‐Hispanic, limiting its generalizability.

In summary, we demonstrate the utility of DAT SBR measures to identify individuals with iRBD at short‐term risk for aSN diagnosis in an international multicenter study. These findings provide the rationale for the next stage of PPMI, ⁴⁰ which will recruit a larger and more diverse sample, including individuals with iRBD with and without abnormal DAT binding. Future work will incorporate clinical features, biological fulid biomarkers, additional imaging biomarkers, and genetic determinants to synthesize multimodal models that can identify a group of iRBD individuals most appropriate to enroll in clinical trials for disease prevention, and to serve as outcome measures for such trials.

Conflict of Interest

None of the authors report a potential conflict of interest related to this work.

Funding Statement

This work was funded by Michael J. Fox Foundation for Parkinson's Research grant .