Objective: To determine the degree of striatal degeneration that occurs in subjects with REM Sleep Behavior Disorder (RBD) and assess whether this is an appropriate population to test neuroprotective treatment strategies for Parkinson’s disease (PD).

Background: The motor deficits associated with PD are caused by a lack of dopamine being delivered from the substantia nigra pars compacta to the striatum. This is caused by the degeneration of the axons and synapses in the striatum (i.e. striatal degeneration). To date attempts at developing disease-modifying therapies for PD have ended in failure. A major reason for these failures is because at the time of clinical diagnosis of PD the loss of axons and synapses is very significant. Some estimates put the number of surviving neurons as low 30-50%. For disease modifying neuroprotective strategies to be successful there needs to be axons/synapses to protect. Therefore for the neuroprotective strategies to be successful they need to be started prior to the onset of clinically defined PD.

Method: Neurologically healthy, RBD, dementia with Lewy bodies, and PD participants underwent ¹⁸F-(+)Fluropropyldihydrotetrabenazine ([¹⁸F]AV-133) positron emission tomography imaging to determine the degree of striatal degeneration, as well as neurophysiological, and neuropsychological testing.

Results: There was reduced VMAT2 in patients with RBD in the caudate and putamen, indicating striatal degeneration in these subjects had commenced. The RBD patients also demonstrated olfactory impairments and increased anxiety, non-motor symptoms typically associated with PD. The RBD patients did not exhibited the overt motor impairments associated with PD.

Conclusion: Neuroprotective treatment strategies are designed to protect what is present, not restore/replace dead connections and testing these treatments where advanced degeneration has occurred dooms these approaches to failure. The ideal subjects are those where striatal degeneration has begun but not progressed so far as to cause irreversible damage leading to profound motor impairments. The striatal neurodegeneration in RBD participants has not yet reached the degenerative threshold for motor impairment demonstrating that these subjects fit this criteria.  Therefore we believe that clinical trials of neuroprotective treatments with the goal of halting PD progression need to be tested in cohorts that are enriched with RBD subjects.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/reduced-striatal-vmat2-in-rem-sleep-behavior-disorder-a-gateway-to-preclinical-parkinsons-disease/