EDITORIAL

The “when” and “where” of α-synucleinopathies

Insights from REM sleep behavior disorder
Mark W. Mahowald, MD, and Carlos H. Schenck, MD Correspondence
Dr. Mahowald
®
Neurology 2018;91:435-436. doi:10.1212/WNL.0000000000006129 [email protected]

Since its identification more than 3 decades ago, REM sleep behavior disorder (RBD) has RELATED ARTICLE
graduated from being a clinical description of a novel and fascinating experiment in nature to
become one of the most important early biomarkers for α-synucleinopathies (Parkinson disease REM behavior disorder
[PD], dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure).1 The predicts motor progression
unique features of RBD as a biomarker are: (1) its ease and accuracy of diagnosis and specificity and cognitive decline in
Parkinson disease
(at least 80% of individuals with apparently “idiopathic RBD” will develop one of these con-
ditions); and (2) the protracted interval between appearance and onset of the more classic Page 437
clinical symptoms (often 10–20 or more years).2,3

The excellent report in this issue by Pagano et al.4 provides further insight into RBD in
particular, and α-synucleinopathies in general. This meticulous study evaluated 421 drug-
naive patients with PD and 196 controls without PD by SPECT presynaptic dopaminergic
imaging; CSF assessment of α-synuclein, total tau, tau phosphorylated at Thr181, and
β-amyloid 1–42 levels; and 3-tesla MRI scan with extensive clinical assessment. Probable
RBD (pRBD) was identified by the RBD Screening Questionnaire, a validated clinical
instrument.

Over a 60-month longitudinal analysis, the presence of pRBD was a predictor of motor
progression and cognitive decline. Greater α-synuclein and dopaminergic pathology was
associated with faster progression of motor symptoms, whereas greater α-synuclein and
amyloid pathology was associated with faster cognitive decline. The severity of pRBD
symptoms correlated with amyloid pathology (lower CSF β-amyloid 1–42 levels). Un-
fortunately, although differences in CSF β-amyloid 1–42 between those PD patients with and
without pRBD were statistically significant, the degree of overlap between the 2 groups would
preclude clinical utility.

The strengths of this study include the large number of drug-naive patients with PD (both with
and without pRBD) and the wide range of clinical, imaging, and CSF parameters studied. One
limitation is the use of a validated RBD questionnaire rather than formal polysomnography to
identify those patients with RBD. The authors did not comment on the fact that 18.3% of
controls showed the presence of pRBD symptoms.

Many “nonmotor” antecedent signs or symptoms of PD, such as constipation, daytime

sleepiness, impaired visual discrimination, anosmia, depression, memory loss, and anxiety, may
anticipate the classic motor features by more than 1 decade (for an epidemiologic timeline, see
Savica et al.5). Because the early nonmotor manifestations of PD are too nonspecific either in
isolation or in combination to be predictive, numerous studies have attempted to increase the
likelihood that RBD may be predictive of progressive neurodegeneration by combining it with
other nonmotor symptoms of α-synucleinopathies.2

It should be mentioned that the established relationship between RBD and psychiatric disease,
particularly depression, remains complex. Some antidepressant medications may be associated
with the appearance of RBD, and psychiatric disease per se (for which the antidepressants were

From the University of Minnesota Medical School, Minneapolis.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.

Copyright © 2018 American Academy of Neurology 435

Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 prescribed) may be a risk factor for the later development of ongoing research studies such as the Pagano et al. study will
neurodegeneration. Therefore, the development of RBD provide the necessary additional preliminary data to rein-
concomitant with antidepressant medication may either be vigorate pharmaceutical industry interest.
due to the medication itself or an early indication of un-
derlying neurodegenerative disease or a combination of both.6 Author contributions
MWM/CHS: Drafting/revising the manuscript.
Although RBD has historically been viewed as a “precursor”
or “prodromal symptom” of α-synucleinopathies, there is Study funding
now compelling evidence that rather than being a harbinger, No targeted funding reported.
pRBD even occurring in isolation is an indication of an al-
ready established α-synucleinopathy.7,8 RBD symptoms do Disclosure
not “precede,” but actually define the onset of an α-synu- M. Mahowald has served on the editorial boards of Sleep and
cleinopathy. Although RBD may also be the manifestation of Sleep Medicine. C. Schenck has served on the editorial boards of
other neurologic conditions, the associated clinical findings Sleep, the Libyan Journal of Medicine, and Sleep Science; and is
due to the underlying condition would render confusion a consultant for Axovant Sciences, Inc. Go to Neurology.org/N
with α-synucleinopathy–related RBD highly unlikely. for full disclosures.

In addition to raising the question of when α-synucleinopathies References

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436 Neurology | Volume 91, Number 10 | September 4, 2018 Neurology.org/N

Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
The ''when'' and ''where'' of α-synucleinopathies: Insights from REM sleep behavior
disorder
Mark W. Mahowald and Carlos H. Schenck
Neurology 2018;91;435-436 Published Online before print August 8, 2018
DOI 10.1212/WNL.0000000000006129

This information is current as of August 8, 2018

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