Longitudinal network changes and phenoconversion risk in isolated REM sleep behavior disorder

Abstract

Isolated rapid eye movement sleep behavior disorder is a prodrome of α-synucleinopathies. Using positron emission tomography, we assessed changes in Parkinson's disease-related motor and cognitive metabolic networks and caudate/putamen dopaminergic input in a 4-year longitudinal imaging study of 13 male subjects with this disorder. We also correlated times to phenoconversion with baseline network expression in an independent validation sample. Expression values of both Parkinson's disease-related networks increased over time while dopaminergic input gradually declined in the longitudinal cohort. While abnormal functional connections were identified at baseline in both networks, others bridging these networks appeared later. These changes resulted in compromised information flow through the networks years before phenoconversion. We noted an inverse correlation between baseline network expression and times to phenoconversion to Parkinson's disease or dementia with Lewy bodies in the validation sample. Here, we show that the rate of network progression is a useful outcome measure in disease modification trials.

Fig. 1. Longitudinal changes in metabolic network expression and dopamine transporter (DAT) binding.

a Expression values (mean ± SEM) for the PD-related metabolic pattern (PDRP, left) and the PD-related cognition pattern (PDCP, right) are displayed for the iRBD cohort at baseline (n = 13), 2 years (n = 12), and 4 years (n = 10) and compared with healthy control (HC1; n = 17) values (see text). Significant increases are observed over time for both networks (PDRP: p = 0.0059; PDCP: p = 0.0031; one-way RMANOVAs, two-sided). [Network expression at each timepoint was z-scored with respect to corresponding HC1 values.] b DAT binding (mean ± SEM) in the putamen (left) and caudate (right) are displayed for the iRBD subjects at each timepoint (baseline: n = 12; 2 years: n = 10), and 4 years (n = 6) and compared to healthy control (HC2; n = 10) subjects (see text). Significant declines were observed over time in both regions (putamen: p = 0.0121; caudate: p = 0.0116; one-way RMANOVAs, two-sided). [iRBD = Isolated rapid eye movement sleep behavior disorder. DAT binding at each timepoint was expressed as the percentage of the healthy control (HC2) mean for each region. Changes over time are represented by horizontal arrows. Differences from healthy control values at each timepoint are represented by asterisks (*p < 0.05, **p < 0.01; two-sample Student’s t-tests, two-sided). Source data are provided as a Source Data file.]

Fig. 2. Metabolic connections gained at each timepoint in the iRBD cohort.

PDRP and PDCP nodes (represented respectively by red and purple spheres) are displayed, with the radius of each node proportional to the degree centrality (number of connections) at each timepoint (TP). Significant connections gained at each timepoint compared to healthy subjects (Supplementary Table 1a–c) are represented by yellow lines, with thickness proportional to the strength of the connections (see Methods). Normal connections between network nodes are represented by cyan lines. [PDRP = PD-related metabolic pattern. PDCP = PD-related cognition pattern. iRBD = isolated rapid eye movement sleep behavior disorder.]

Fig. 3. Gain and loss of functional connections within and between the PDRP and PDCP networks.

a Left: The majority of gained connections (see Methods) were between PDRP nodes in the iRBD subjects at baseline (n = 13; gray), but the proportion (% total; mean ± SEM) of PDRP–PDRP connections declined incrementally at the 2-year (n = 12; green) and 4-year (n = 10; orange) timepoints. Middle: Over the same time period, stepwise increases in gained connections were observed between PDRP and PDCP nodes (PDRP–PDCP). Right: By contrast, proportionally fewer connections were gained between PDCP nodes (PDCP–PDCP), with declines in this category of connections over time. b The percentage of healthy connections (mean ± SEM; see Methods) that were lost in the iRBD subjects at baseline (n = 13; gray) was similar for PDRP–PDRP (left) and PDRP–PDCP (middle) categories. However, the proportion of lost connections increased in the former category and declined in the latter over 2 (n = 12; green) and 4 (n = 10; orange) years. Loss of healthy PDCP–PDCP connections over time (right) was less than for the other connection categories, with no significant change over time. [n.s.=non-significant, *p < 0.05, **p < 0.01, ***p < 0.001, post-hoc Bonferroni tests, corrected for multiple comparisons, after one-way ANOVA, two-sided. PDRP = PD-related metabolic pattern. PDCP = PD-related cognition pattern. iRBD = isolated rapid eye movement sleep behavior disorder. Source data are provided as a Source Data file.]

Fig. 4. PDRP and PDCP network metrics at each timepoint.

Relevant network metrics were plotted for (a) PDRP and (b) PDCP. For each network, mean degree centrality (left), small-worldness (middle), and assortativity (right) were plotted for the iRBD subjects at baseline (n = 13, black), 2 years (n = 12, green), and 4 years (n = 10, orange); corresponding mean values in the healthy control (HC1; n = 17) group are provided for reference (gray). [Differences between groups or timepoints were evaluated using the general linear model across graph thresholds, two-sided, with post-hoc Bonferroni corrections for multiple comparisons (see Methods); post-hoc differences from HC1 at each of the three timepoints for the iRBD cohort are represented by asterisks (*p < 0.05, **p < 0.01, ***p < 0.001); post-hoc differences from baseline at 2 and 4 years for the iRBD cohort are represented by crosses (†p < 0.05, ††p < 0.01, †††p < 0.001). PDRP = PD-related metabolic pattern. PDCP = PD-related cognition pattern. iRBD = isolated rapid eye movement sleep behavior disorder. Source data are provided as a Source Data file.]

Fig. 5. Correlation with the time from imaging to phenoconversion.

a The time to phenoconversion (years) from the imaging study correlated inversely (n = 12, r = −0.58, p = 0.0486; Pearson correlation, two-sided) with PDRP expression measured at baseline in the 12 iRBD subjects from the cross-sectional cohort who subsequently phenoconverted to PD (n = 8; circles) or DLB (n = 4; triangles). b Leverage plot analysis (n = 11; one of the 12 iRBD subjects was excluded from this analysis due to missing UPDRS motor rating) further illustrates the significant inverse correlation of the time to phenoconversion with PDRP expression after controlling for age, sex, UPDRS motor ratings, and iRBD duration (r = −0.55, p = 0.0131; partial correlation, two-sided). c, d Leverage plots show additional correlations of the time to phenoconversion with baseline UPDRS motor ratings (r = −0.41, p = 0.0297; partial correlation, two-sided) and age (r = −0.58, p = 0.0138; partial correlation, two-sided). Correlations with sex (p = 0.7480; partial correlation, two-sided) and iRBD duration (p = 0.5191; partial correlation, two-sided) were not significant. [In the leverage plots, circles and triangles refer to iRBD subjects who later phoenoconvert to PD or DLB. PDRP = PD-related metabolic pattern. iRBD isolated rapid eye movement sleep behavior disorder. UPDRS Unified Parkinson’s Disease Rating Scale. PD Parkinson’s disease. DLB dementia with Lewy bodies. Source data are provided as a Source Data file.]

Fig. 6. Phenoconversion risk in iRBD subjects.

PDRP expression values (y-axis) were plotted against putamen DAT binding measurements (x-axis) recorded at the final imaging timepoint for the longitudinal iRBD subjects (n = 12). Four iRBD subjects converted to PD (Subjects #1-3; black circles) or DLB (Subject #4; black triangle) within 7 years after the final imaging timepoint (see text). The remaining 8 iRBD participants (open circles) did not phenoconvert during the observational phase of the study. Shaded arrow bars indicate the hypothetical risk of phenoconversion ranging from low to high, associated with higher PDRP expression (left side vertical bar) and lower putamen DAT binding (top horizontal bar) in iRBD subjects (see text). [The “PD zone” (top left) was defined based on historical data of early-stage PD patients, for whom PDRP expression was typically greater than +1.5 and putamen DAT binding was below 40% of normal mean (solid black lines) (see text). iRBD isolated rapid eye movement sleep behavior disorder. PDRP PD-related metabolic pattern. DAT dopamine transporter. PD Parkinson’s disease. DLB dementia with Lewy bodies. Source data are provided as a Source Data file.]