Cutaneous Alpha-Synuclein is Correlated with Autonomic Impairment in Isolated REM Sleep Behavior Disorder

Abstract Study Objectives To define the clinical implications of cutaneous phosphorylated α-synuclein (p-syn) and its association with subjective and objective measures of autonomic impairment and clinical features including antidepressant use in isolated REM sleep behavior disorder (iRBD). Methods Twenty-five iRBD patients had quantified neurological and cognitive examinations, olfactory testing, questionnaires, autonomic function testing, and 3 punch skin biopsies (distal thigh, proximal thigh, neck). Skin biopsies were stained for the pan-axonal marker PGP 9.5 and co-stained with p-syn, and results were compared to 28 patients with Parkinson’s disease (PD) and 18 healthy controls. Equal numbers of iRBD patients on and off antidepressants were recruited. The composite autonomic severity scale (CASS) was calculated for all patients. Results P-syn was detected in 16/25 (64%) of iRBD patients, compared to 27/28 (96%) of PD and 0/18 controls. The presence of p-syn at any biopsy site was correlated with both sympathetic (CASS adrenergic r = 0.6, p < 0.05) and total autonomic impairment (CASS total r = 0.6, p < 0.05) on autonomic reflex testing in iRBD patients. These results were independent of the density of p-syn at each site. There was no correlation between p-syn and antidepressant use. Conclusions In patients with iRBD, the presence of cutaneous p-syn was detected in most patients and was associated with greater autonomic dysfunction on testing. Longitudinal follow-up will aid in defining the predictive role of both skin biopsy and autonomic testing in determining phenoconversion rates and future disease status.

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REM sleep behavior disorder and other sleep abnormalities in p. A53T SNCA mutation carriers

SLEEP ◽

10.1093/sleep/zsaa248 ◽

2020 ◽

Author(s):

Athina Maria Simitsi ◽

Christos Koros ◽

Maria Stamelou ◽

Dimitra Papadimitriou ◽

Athanasios Leonardos ◽

...

Keyword(s):

Sleep Disorder ◽

Rem Sleep ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Alpha Synuclein ◽

Sleep Behavior ◽

Asymptomatic Carriers ◽

Olfactory Testing ◽

Obstructive Sleep ◽

Sleep Abnormalities

Abstract Study Objectives Τo assess whether REM Sleep Behavior Disorder (RBD) and other sleep abnormalities occur in carriers of the p.A53T alpha-synuclein gene (SNCA) mutation, using both subjective and objective measures. Methods We have assessed 15 p.A53T carriers (10 manifesting Parkinson’s Disease [PD-A53T] and 5 asymptomatic carriers) with simultaneous Video-PSG (polysomnography) recording, the Epworth Sleepiness Scale (ESS) for daytime sleepiness, the Athens Insomnia Scale (AIS), the RBD Screening Questionnaire (RBDSQ) for clinical features of RBD, the Montreal Cognitive Assessment (MOCA) for cognition and the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction. Results In our cohort, 90% of PD carriers had at least one sleep disorder and 40% had two: 4 RBD, 1 Periodic Limb Movements (PLM), 1 RBD plus PLM, 2 RBD plus moderate Obstructive Sleep Apnea (OSA), and 1 moderate OSA plus Restless Leg Syndrome. No asymptomatic carrier manifested a confirmed sleep disorder. 6/7 PD carriers with RBD had abnormal olfactory testing and 4/7 MOCA below cut off. There was a correlation of both impaired olfaction and cognition with RBD. Conclusions RBD occurs in the majority of PD-A53T, in contrast to most other genetic forms of PD, in which RBD is uncommon. The paucity of a sleep disorder in the asymptomatic carriers suggests that such carriers have not yet reached the prodromal phase when such sleep disorders manifest. Hyposmia in almost all subjects with RBD and cognitive decline in most of them are indicative of the general pattern of disease progression, which however is not uniform.

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Alpha-synuclein aggregates in the parotid gland of idiopathic REM sleep behavior disorder

Sleep Medicine ◽

10.1016/j.sleep.2018.08.003 ◽

2018 ◽

Vol 52 ◽

pp. 14-17 ◽

Cited By ~ 6

Author(s):

Ana Fernández-Arcos ◽

Isabel Vilaseca ◽

Iban Aldecoa ◽

Mónica Serradell ◽

Eduard Tolosa ◽

...

Keyword(s):

Parotid Gland ◽

Rem Sleep ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Alpha Synuclein ◽

Sleep Behavior

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0787 Autonomic Dysfunction and Phenoconversion in Idiopathic/Isolated REM Sleep Behavior Disorder

SLEEP ◽

10.1093/sleep/zsaa056.783 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A300-A300

Author(s):

S McCarter ◽

T Gehrking ◽

E St. Louis ◽

M Suarez ◽

B Boeve ◽

...

Keyword(s):

Autonomic Dysfunction ◽

Rem Sleep ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Common Finding ◽

Chi Square ◽

Sleep Behavior ◽

Autonomic Testing ◽

Function Testing

Abstract Introduction REM-sleep behavior disorder (RBD) is a common finding among patients with synucleinopathies. We aimed to determine the degree of autonomic dysfunction in patients presenting with idiopathic RBD (iRBD), and the predictive value of autonomic dysfunction for phenoconversion to a defined neurodegenerative disease. Methods We searched our electronic medical record for patients diagnosed with iRBD who also underwent standardized autonomic function testing within 6 months of iRBD diagnosis, and who had clinical follow-up of at least 3 years following iRBD diagnosis. Patients who received a diagnosis of phenoconversion within 3 months of autonomic testing were excluded. The composite autonomic severity score (CASS) was derived and compared between phenoconverters and non-converters using chi-square and Wilcoxon rank-sum tests. Results We identified 18 patients who fulfilled in- and exclusion criteria. Average age at autonomic testing was 67 ± 6.6 years. Twelve (67%) patients phenoconverted during the follow-up period; 6 developed PD, the other 6 DLB. Fifteen (83%) patients had at least mild autonomic dysfunction. There were no significant differences between overall converters and non-converters in total CASS or CASS subscores. However, iRBD patients who developed DLB had significantly higher total and cardiovagal CASS scores compared with those who developed PD (p <0.05), and a trend for higher adrenergic CASS scores compared to those who developed PD and those who did not phenoconvert (p=0.08 for each). Conclusion Autonomic dysfunction was seen in 83% of iRBD patients, and more severe baseline cardiovagal and adrenergic autonomic dysfunction in iRBD was associated with phenoconversion to DLB but not PD. Prospective studies are needed to confirm the value of autonomic testing for predicting phenoconversion and disease phenotype in iRBD. Support

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Predicting alpha-synuclein pathology by REM sleep behavior disorder diagnosis

Parkinsonism & Related Disorders ◽

10.1016/j.parkreldis.2018.05.020 ◽

2018 ◽

Vol 55 ◽

pp. 92-96 ◽

Cited By ~ 7

Author(s):

David R. Shprecher ◽

Charles H. Adler ◽

Nan Zhang ◽

Joseph G. Hentz ◽

Geidy E. Serrano ◽

...

Keyword(s):

Rem Sleep ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Alpha Synuclein ◽

Sleep Behavior

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Morbidity, Mortality, and Conversion to Neurodegenerative Diseases in Patients with REM Sleep Behavior Disorder and REM Sleep without Atonia

Neuroepidemiology ◽

10.1159/000514175 ◽

2021 ◽

Vol 55 (2) ◽

pp. 141-153

Author(s):

Cresta Asah ◽

Rune Frandsen ◽

Rikke Ibsen ◽

Jakob Kjellberg ◽

Poul Jennum

Keyword(s):

Neurodegenerative Diseases ◽

Rem Sleep ◽

Metabolic Diseases ◽

Neurodegenerative Disorder ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Alpha Synuclein ◽

Morbidity Rate ◽

Sleep Behavior ◽

Before And After

Introduction: The underlying pathophysiology of idiopathic REM sleep behavior disorder (iRBD) is not fully understood, although the condition is currently recognized as an early-stage alpha-synuclein disorder. We evaluated the morbidity, mortality, and rate of conversion to a neurodegenerative disorder in a national group of patients. Methods: All patients in Denmark with a diagnosis of RBD between 2006 and 2013 were identified from the Danish National Patient Registry (NPR) records. We excluded patients who had received a diagnosis of narcolepsy or any of the following neurodegenerative diseases before their diagnosis of RBD: Parkinson’s disease, multiple system atrophy, progressive supranuclear paralysis, Alzheimer’s, and Lewy body dementia. We used randomly chosen controls matched for age, gender, and municipality. Results: In total, 246 iRBD patients and 982 matched controls were analyzed. The mortality rate was the same in both groups. The morbidity rate was significantly higher in the years before and after an RBD diagnosis, due to a wide variety of disorders in the following major disease groups: mental/behavioral disorders; endocrine/metabolic diseases; diseases of the eye; diseases of the nervous, digestive, musculoskeletal, circulatory, and respiratory systems; abnormal findings not classified elsewhere; external causes; and factors influencing health status. The conversion rate from RBD to a neurodegenerative disease was 13% over the 8 years after a diagnosis of RBD. Conclusions: A diagnosis of RBD is associated with increased morbidity several years before and after a diagnosis is made. Patients have a higher risk of converting to a neurodegenerative disorder than matched controls. Mortality rates are unchanged.

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533 Characteristics of patients with REM sleep without atonia (RSWA)/persistent periodic limb movements of sleep (PLMS) in REM sleep

SLEEP ◽

10.1093/sleep/zsab072.531 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A209-A211

Author(s):

Lina Barker ◽

Maja Tippmann-Peikert

Keyword(s):

Rem Sleep ◽

Psychiatric Diagnosis ◽

Neurological Disorders ◽

Neurological Diseases ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Periodic Limb Movements ◽

Sleep Behavior ◽

Exact Test ◽

Antidepressant Use

Abstract Introduction While RSWA in REM sleep behavior disorder (RBD) is associated with male sex, age > 50 years, alpha-synucleinopathies, and narcolepsy, the characteristics of patients with RSWA/PLMS in REM sleep (RSWA/PLMS-REM) without dream enactment behaviors are unexplored. The aim of this study was to compare the demographics, comorbidities and concomitant medication use between RSWA/PLMS-REM patients and non-RSWA/non-PLMS-REM controls. Based on anecdotal clinical observations we hypothesized that these patients are more commonly young, women, have psychiatric or neurological diseases, and use antidepressants. Methods We conducted a retrospective review of the Mayo Clinic electronic medical record to identify all patients with RSWA/ PLMS-REM between November 2018 and November 2020. After excluding all patients with RBD, restless legs syndrome, narcolepsy and RSWA/non-PLMS-REM we identified 27 patients. All PSGs were reviewed to calculate the periodic limb movement index per hour of REM sleep (REM-PLMI). We also identified a covenience sample of 15 non-RSWA controls, reviewed their PSGs and calculated REM-PLMI. Results The mean REM-PLMI of patients with RSWA was 64+/-8.3 (SEM)/hour versus 1+/-0.6 (SEM)/hours in non-RSWA controls (p< 0.001). Patients with RSWA/PLMS-REM and non-RSWA controls had similar age and gender, 62 +/- 3 (SEM) versus 58 +/-3 (SEM) years and 81% versus 87% men, respectively. However psychiatric diagnosis, neurological disorders and antidepressants use was more common among RSWA/PLMS-REM patients compared to non-RSWA controls, p=0.0002, p=0.0035 and p=0.0074, respectively. (Fisher’s Exact Test) Conclusion Psychiatric diagnosis, neurological disorders and antidepressant use are more common among RSWA/PLM-REM patients compared to non-RSWA controls. Further research to determine the implications of a diagnosis of RSWA/PLMS-REM for the future development of alpha-synucleinopathies are needed and currently ongoing. Support (if any):

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Acting out Dreams: REM Sleep Behavior Disorder

Dementia with Lewy Body and Parkinson's Disease Patients ◽

10.1093/oso/9780199977567.003.0027 ◽

2013 ◽

Author(s):

J. Eric Ahlskog

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Multiple System Atrophy ◽

Rem Sleep ◽

Sleep Stage ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Alpha Synuclein ◽

Sleep Behavior ◽

The Brain

Normal dreaming occurs during the deepest sleep states. Obviously, if experiencing a frightening dream, sleeping people could be injured if they jumped out of bed and started to run. Fortunately, the brain has a natural protective mechanism during dreaming: body paralysis. During the primary sleep stage in which dreaming occurs, the body’s muscle tone is shut off and muscles become limp. Only the eye muscles are spared, still able to move during a dream. This state in which dreaming takes place is rapid eye movement (REM) sleep. Restated, during REM sleep, a switch is thrown in the brain stem that shuts off body movement during dreaming. People with Lewy disorders of all types often lose this switch function. In other words, they can still move during the dreams of REM sleep. In the midst of a dream, they may act out by yelling, kicking, or hitting the air. This behavior is termed dream enactment behavior. When it is a recurring event it is termed REM sleep behavior disorder. REM sleep behavior disorder occurs in people with Lewy disorders—Parkinson’s disease, DLB, or PDD. It also occurs in another disorder in which alpha-synuclein is abnormally deposited in the nervous system, multiple system atrophy (MSA). Recall from Chapter 2 that alpha-synuclein is present in Lewy bodies and is thought to be a causative factor in all of these conditions. REM sleep behavior disorder may be present years or even decades before the occurrence of DLB, PDD, Parkinson’s disease, or multiple system atrophy. It is often one of the first signs of these disorders, predating most other manifestations. That does not mean that everyone who acts out their dreams will eventually develop Parkinson’s disease, DLB, or MSA. However, it does confer an increased risk. It should be noted that certain medications may provoke REM sleep behavior disorder, such as the commonly used antidepressants. Also, sleepwalking in children should not be confused with this disorder. Sleepwalking occurs in a different sleep stage and is not thought to be a forerunner of Lewy body conditions.

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