By Alan Z. Segal, MD

Associate Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Segal reports no financial relationships relevant to this field of study.

SYNOPSIS: Rapid eye movement behavior disorder carries an increased risk of future Parkinson’s disease and has fMRI and DaTSCAN features that are similar to those in patients with Parkinson’s disease.

SOURCE: Rolinski M, Griffanti L, Piccini P, et al. Basal ganglia dysfunction in idiopathic REM sleep behavior disorder parallels that in early Parkinson’s disease. Brain 2016;139:2224-2234.

Rapid eye movement (REM) behavior disorder (RBD) is a syndrome in which patients fail to suppress muscle activity during REM sleep. As a consequence, they act out their dreams. It has been shown that RBD may be a precursor to neurodegenerative disease, specifically the “α-synucleinopathies” — Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. Therefore, RBD may represent a preclinical state of basal ganglia decline.

Rolinski et al used functional MRI (fMRI) to demonstrate that, when compared to controls, RBD patients show the same pattern of activity as patients who already have early PD. In typical fMRI studies, increased metabolic activity of the brain is observed when a subject is asked to perform a variety of tasks while inside the magnet. The brain “lights up,” showing increased BOLD (blood oxygen level dependent) signals in correspondingly activated motor, sensory, visual, and association cortices. In the current study, subjects are passive in the scanner, and a resting state (RS)-fMRI pattern is observed. Using a technique called dynamic causal modeling, a series of spontaneously occurring, slow changes are observed in regions of the brain that are architecturally distinct but have strong functional connectivity. Abnormalities in this connectivity may be detected at rest without the use of any specific activation paradigm.

In PD, the basal ganglia network (BGN) identifies a pattern of activation seen on RS-fMRI that involves the caudate, putamen, pallidum, subthalamic nucleus, and supplementary motor area. The RS-fMRI of the BGN previously has been shown to differentiate PD from controls, with excellent sensitivity and moderate specificity. Interestingly, while RS-fMRI may lack specificity, alternative fMRI techniques (known as seed-based methods) achieve specificity by selecting very specific voxels for analysis. These are distinctly different from RS-fMRI of the BGN, which is a more integrative, widely distributed imaging method.

In this study, RBD patients (n = 26) showed a BGN pattern that was convincingly similar to PD patients (n = 46) and different from controls (n = 23). In fact, while the sensitivity of this pattern for RBD and PD was equal (96% for both), the pattern was slightly more specific for RBD (78%) than it was for PD (74%) in comparison to controls.

The fMRI data in this study were supplemented in a subset of subjects with DaTSCAN imaging (RBD n = 8, PD n = 10, and controls n = 10). DaTSCANs are single photon emission tomography (SPECT) images using the tracer 123I-ioflupane, which has a high affinity for presynaptic dopamine transporters. PD patients showed reduced average DAT uptake values when compared to controls (for example, 2.47 vs. 3.43 in the caudate and 1.86 vs. 3.10 in the putamen). RBD patients fell into an intermediate range (3.19 and 2.69 in the caudate and putamen, respectively), which were above that seen with PD, but below control norms. However, these findings for RBD did not reach statistical significance, likely because of small numbers.

There have been limited prior studies in RBD using other tracers, such as fluorodopa PET activity as well as 11C dihydrotetrabenazine (11C -DTBZ) — both suggesting loss of dopaminergic neurons. In the current study, using detailed morphometric analysis, neither RBD or PD could be differentiated structurally from controls.

COMMENTARY

All of these data suggest that RBD may represent prodromal PD in patients who are completely normal in the waking state. It is challenging to know how to counsel any RBD patient regarding PD risk and, even more challenging, to counsel patients without overt RBD whose only abnormality is the finding of REM sleep without atonia (RSWA) on a polysomnogram (PSG). Such PSG-positive RSWA may manifest either as subtle, but clinically apparent, periodic limb movements in non-REM sleep that continue in REM, or as clinically silent surface EMG muscle activity. Neither of these phenomena are apparent to the subject or their bed partner.

Sleep is a physiologically unique state in which movement disorders behave differently than in wake. Therefore, it might be interesting to perform fMRI in sleep (ideally both during REM and non-REM phases), as this might shed light on the unique fact that PD tends to be “silent” when the brain is asleep. Such data also may suggest how REM-related movement is giving us a clue to the earliest stages of basal ganglia dysfunction.

As this study suggests, the connection between RBD and PD is deserving of further investigation. If RBD is a reliable precursor of PD, lengthier longitudinal studies would be possible and, more importantly, neuroprotective disease-modifying therapies could be developed.