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Volume 14 No. 10
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Accepted Papers





Scientific Investigations

Sleep Architecture Changed Without RBD in Patients With FTDP-17

Jia Liu, MD, PhD1; Shuqin Zhan, MD1; Chaoyang Huang, MD1; Yang Liu, MD1; Lin Liu, MD1; Liyong Wu, MD1,2; Yuping Wang, MD1
1Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China; 2National Clinical Research Center for Geriatric Disorders, Capital Medical University, Beijing, China

ABSTRACT

Study Objectives:

The aim of this study is to detect the features of sleep disorder via polysomnography (PSG) based on Chinese pedigree of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).

Methods:

Five members (two symptomatic patients and three patients with a presymptomatic mutation) from the FTDP-17 pedigree were enrolled, in comparison with 9 patients with Parkinson disease (PD) and 11 control patients. Each patient underwent standard PSG and hypnogram analysis.

Results:

Sleep architecture is affected in the presymptomatic stage of FTDP-17, including total sleep time and sleep efficiency. However, rapid eye movement sleep behavior disorder seems to be exempt from FTDP-17. In hypnogram analysis, five individuals with FTDP-17 exhibited decreased sleep efficiency and disruption of the normal cyclic sleep organization.

Conclusions:

In FTDP-17, striatum and brainstem are the pathological lesions, which may be involved in the pathophysiology of the alterations in sleep architecture. The concrete mechanisms need further investigation.

Citation:

Liu J, Zhan S, Huang C, Liu Y, Liu L, Wu L, Wang Y. Sleep architecture changed without RBD in patients with FTDP-17. J Clin Sleep Med. 2018;14(10):1735–1739.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Rapid eye movement sleep behavior disorder (RBD) and sleep architecture changes are common in neurodegenerative diseases. The features of sleep disorder in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) are still unknown and need to be investigated via polysomnography and hypnogram analysis.

Study Impact: Sleep architecture is affected even in the presymptomatic stage of FTDP-17, but RBD seems to be exempt from FTDP-17. Striatum and brainstem are the pathological lesions in FTDP-17 and may be involved in the pathophysiology of sleep alterations.

INTRODUCTION

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is a rare autosomal dominant neuro-degenerative disorder.1 Most cases are caused by mutations in the microtubule-associated protein tau (MAPT); more than 50 pathogenic MAPT mutations have been found. FTDP-17 neuropathology illustrates neuronal and glial tau-rich inclusions in both neocortical and subcortical regions.2 Therefore, FTDP-17 with MAPT mutations is classified as tauopathy together with other common neurodegenerative diseases, such as Alzheimer disease (AD), argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration.3,4 In contrast, Parkinson disease (PD) and multiple system atrophy are synucleinopathy with neuronal or glial α-synuclein pathology.5

The relationship of neurodegeneration and sleep disorders has been intensively investigated in recent years. For instance, rapid eye movement sleep behavior disorder (RBD) has been proven to be an early manifestation of—and to predict the progression of—neurodegenerative diseases with synucleinopathy.6,7 As a tauopathy, AD is associated with changes in sleep architecture such as increased wake as well as decreased non-rapid eye movement (NREM) and REM sleep. RBD can also occur in AD but is relatively rare.8 Concerning FTDP-17, no RBD or REM sleep without atonia (RSWA) was found in a previous study based on the pedigree originating in colonial Virginia.9 The details of sleep architecture are still unclear. In our study, we aim to detect the features of sleep disorder via polysomnography (PSG) based on Chinese FTDP-17 pedigree and compare with the findings in patients with PD.

METHODS

Ethics and Participants

This study was approved by the Ethics Committee, Xuanwu Hospital, Capital Medical University, China. Informed consents were signed by the participants and the next of kin. A previously reported Chinese FTDP-17 pedigree with the N279K mutation in MAPT including five patients (two symptomatic patients and three presymptomatic mutation carriers) were enrolled.10 Nine patients with PD and 11 control patients were matched for the comparison. The diagnosis of PD followed UK brain bank criteria. Control patients were free of any neurological diseases.

Polysomnography and Hypnogram Analysis

Each patient underwent standard video PSG (E-Series, Compumedics Limited, Abbotsford, Australia). The PSG system included continuous recordings of electroencephalography (EEG), electrooculography, submental and anterior tibial electromyography (EMG), nasal/oral airflow, chest/abdominal respiratory effort, electrocardiography, and percutaneous oxygen saturation. Involuntary limb movements during sleep were recorded by video monitoring, and periodic limb movements in sleep (PLMS) were scored from EMG. EMG activity was scored using the following criteria: (1) tonic EMG activity: each 30-second epoch was scored as tonic if tonic EMG activity was detected for more than 50% of the epoch; (2) phasic EMG density: each 30-second epoch was scored and represented the percentage of 3-second mini-epochs containing phasic EMG events. Phasic EMG events were defined as any burst of EMG activity lasting 0.1 to 5 seconds with an amplitude exceeding twice the background EMG activity. These criteria were used to identify all EMG bursts that clearly contrasted with background EMG activity. Sleep structure, sleep efficiency (total sleep time / total time in bed × 100), arousal, PLMS indices (number of arousals and PLMS per hour of sleep), and the apnea-hypopnea index (AHI) were evaluated. Sleep stages (wake, N1, N2, N3, and R) were scored offline according to the American Academy of Sleep Medicine scoring criteria by visual and spectral inspection of 30-second EEG epochs.11,12

Data Analysis

Data analysis was performed using SPSS18.0 (SPSS Inc, Chicago, Illinois, United States) between the two groups (FTDP-17 versus control, as well as FTDP-17 versus PD). To test for heterogeneity of dichotomous data, we used chi-square test. For continuous data, statistical significance was determined by Mann-Whitney U test. Results were considered statistically significant if values of P < .05.

RESULTS

In this study, five members with N279K mutation in MAPT (two symptomatic patients and three with a presymptomatic mutation) were analyzed,10 in comparison with 9 patients with PD and 11 controls. Parkinsonism was the first-onset symptom for the two symptomatic patients. All the participants enrolled in this study underwent PSG analysis. The electrophysiological features of RSWA and behavioral manifestations of RBD were absent in all 5 FTDP-17 members and 11 control patients. In contrast, 4 of 9 patients (44%) patients with PD had electro-physiological features of RSWA and behavioral manifestations of RBD.

The details of demographics and PSG analysis of FTDP-17 members were summarized in Table 1. In summary, abnormal results were widely observed in PSG indices of FTDP-17, such as time in bed, total sleep time (TST), sleep efficiency, percentage of NREM/REM stage, latency to REM sleep, and PLMS index. The reduction in TST was found in all five patients with FTDP-17, and was more drastic in symptomatic patients than in patients with a presymptomatic mutation. The same tendency was seen in sleep efficiency. PLMS index was increased in symptomatic patients. No obstructive apneas were observed. In hypnogram analysis, five patients with FTDP-17 exhibited decreased sleep efficiency and disruption of the normal cyclic sleep organization. Control patients successfully completed several sleep cycles (Figure 1).

Demographic characteristics and PSG in FTDP-17.

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Table 1

Demographic characteristics and PSG in FTDP-17.

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Hypnogram of a healthy control patient and the patients with FTDP-17.

The patients with FTDP-17 presented with decreased sleep efficiency and disruption of the normal cyclic sleep organization (horizontal axis in sleep hours). FTDP-17 = frontotemporal dementia with parkinsonism linked to chromosome 17, N1, N2, N3 = NREM sleep stages, R = REM sleep, W = wake.

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Figure 1

Hypnogram of a healthy control patient and the patients with FTDP-17.

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By statistical analysis, there were no significant differences in age, sex, and body mass index of patients with FTDP-17 compared to patients with PD or control patients (Table 2). In comparison with control patients, those with FTDP-17 were associated with significant changes in TST (P < .001), sleep efficiency (P < .001), percentage of stage N1 sleep (P < .001), percentage of stage R sleep (P = .003), minimum oxygen saturation (P = .038), and AHI (P = .002). In comparison with patients with PD, there were significant changes in TST (P = .007), sleep efficiency (P = .001), percentage of stage N1 sleep (P = .001), and percentage of stage R sleep (P = .029).

PSG comparisons in FTDP-17, PD, and control groups.

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Table 2

PSG comparisons in FTDP-17, PD, and control groups.

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DISCUSSION

To the best of our knowledge, there are few reports analyzing FTDP-17 via PSG.9 This is the first study based on Chinese FTDP-17 pedigree of Han nationality.10 Through the comparisons with control patients and patients with PD, significant sleep structure changes of FTDP-17 were found in TST, sleep efficiency, percentage of stage N1 sleep, and percentage of stage R sleep. In comparison with patients carrying a presymptomatic mutation, TST and sleep efficiency in symptomatic patients were drastically changed and seemed to be associated with disease progression. No electrophysiological features of RSWA and behavioral manifestations of RBD were found in patients with FTDP-17. TST was significantly reduced in symptomatic patients. Our findings are consistent with previous study results that found a decrease in TST and no RBD.9 Therefore, we conclude that sleep architecture has been widely impaired even in the presymptomatic stage of FTDP-17. However, FTDP-17 as a phenotype of tauopathy is proven to be different from synucleinopathy in patients with RBD.

It is generally acknowledged that brainstem and basal ganglia are intensively involved in the pathophysiology of the alterations in sleep architecture. The mechanisms may include the changes of neurotransmitters such as adenosine, dopamine, glutamate, glycine, and γ-aminobutyric acid.13,14 Interestingly, FTDP-17 was previously known as pallidopontonigral degeneration before gene era, according to neuropathological features,1 in which striatum and brainstem are the main pathological lesions. In our previous study of C11-CFT-PET, striatal dopaminergic dysfunction can be seen in presymptomatic FTDP-17 and is a potential biomarker predicting onset,10 which may be also involved in the sleep disorders. In contrast, PD is generally characterized by RBD, which is associated with neuronal network dysfunction in the brainstem. In both AD and PD, the accumulation of pathological protein (tau in AD, alpha-synuclein in PD) started from the brainstem.15,16 Changed sleep architecture is prevalent in AD; however, RBD can be occasionally seen in AD.8 Therefore, the mechanisms of RBD and sleep architecture changes are probably different.

In conclusion, sleep architecture is affected even in the presymptomatic stage of FTDP-17, including TST, sleep efficiency, and PLMS index. However, RBD seems to be exempt from FTDP-17, which is different from AD and PD. The concrete mechanisms need further investigation. The limitations of this study should be considered, such as small sample size and potential bias in participant selection. Our findings are required to be confirmed by future studies.

DISCLOSURE STATEMENT

This work was supported by the National Natural Science Foundation of China (No. 81470074, 81601099), clinical funding from Beijing Municipal Science and Technology Committee (Z141107002514117), Beijing Municipal Government Funding (PXM2017_026283_000002), Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry ([2015] No.1098); Beijing Talents Fund (2015000026833ZK06); Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan (CIT&TCD201804091); Beijing Municipal Administration of Hospitals Youth Program (QML20150801); Clinical-Basic Medicine Cooperation Fund of Capital Medical University (16JL28). The authors report no conflicts of interest.

ABBREVIATIONS

AD

Alzheimer disease

AHI

apnea-hypopnea index

FTDP-17

frontotemporal dementia with parkinsonism-linked to chromosome 17

MAPT

microtubule associated protein tau

NREM

non-rapid eye movement

PD

Parkinson disease

PLMS

periodic limb movements in sleep

PSG

polysomnography

RBD

REM sleep behavior disorder

REM

rapid eye movement

RSWA

REM sleep without atonia

TST

total sleep time

ACKNOWLEDGMENTS

The authors are grateful to the patients and their families for granting us the permission to publish this information.

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