This was a single-center cross-sectional case-control study. Consecutive patients with CSVD were recruited from the outpatient clinic of the Third Affiliated Hospital of Sun Yat-sen University between September 2017 and December 2018. Healthy spouses or siblings of the CSVD patients were enrolled in the healthy control group.
A total of 84 CSVD patients were recruited based on the inclusion/exclusion criteria, along with 24 age- and sex-matched healthy controls. All participants underwent structured interviews and physical examination by a study physician who confirmed the diagnosis. Data pertaining to the following demographic and clinical characteristics were collected for all subjects: age; sex; body mass index (BMI); marital status; occupation; educational status; insomnia conditions (Table 1).
- Age: 50–70 years.
- Presence of at least one of the following cardiovascular risk factors: hypertension, atherosclerosis, diabetes mellitus, past or current smoking.
- Presence of the following symptoms of CSVD: lacunar syndromes, cognitive, motor (gait), dysphagia, or mood disturbances. Subjects who were eligible because of a lacunar syndrome were included only > 3 months after the event to avoid acute effects on the outcomes.
- Evidence of one or more MR markers of CSVD : lacunars, WMHs with Fazekas grade 2 (early confluent) or higher , visible PVSs and CMBs.
- Subjects in the control group had no cardiovascular risk factors, CSVD symptoms, or MR markers of CSVD.
- Provision of written informed consent.
- Patients with larger subcortical or cerebral Water-shed infarctions (>1.5 cm) on MR, as these are often embolic.
- Patients with large artery disease - carotid, vertebral or intracranial stenosis >50%;
- Presence of severe mental disorders such as schizophrenia, bipolar disorder or major depression, alcohol and/or other drug abuse or dependence;
- Presence of uncontrolled somatic disorders or sleep-disrupting comorbid medical conditions (e.g., moderate to severe rheumatoid arthritis); patients who required immediate psychiatric (e.g., imminently suicidal patients) or medical care (e.g., patients with acute cardiac symptoms)
- Patients with breathing-related sleep disorders, restless legs syndrome, or circadian rhythm sleep disorders according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition .
- Apnea-hypopnea index ≥15 or/and periodic limb movement (PLM)-related arousal index ≥15 per hour of sleep during a screening laboratory polysomnogram;
- Patients with CSVD caused by other reasons such as hereditary or inflammatory disorders or amyloidosis.
- Patients who were being treated with medications that affect sleep within two weeks of initial screening. Medications that affect sleep include sleep-promoting medications (e.g., hypnotics/sedatives/neuroleptics/other novel agents) and wakefulness-promoting medications (e.g., modafinil, traditional stimulants).
- Any inability to fulfill study data collection.
Brain MRI scan
The General Electric 3 T superconducting MR scanner with 8 channels, head and neck coils was used for brain scanning. The acquisition sequences included 3D TOF-MRA, MRI T1Flair, T2WI, T2Flair and susceptibility weighted imaging (SWI). Images were rated by a certified and registered neuroradiologist in a blinded manner for the presence of the following four CSVD makers; the presence of each SVD makers was summed in an ordinal “SVD burden score” (range 0–4) .
Lacunes: rounded or ovoid lesions, >3- and <15-mm diameter, in the basal ganglia, internal capsule, centrum semiovale, or brainstem, exhibiting signal intensity of CSF on T2 and FLAIR, generally with a hyperintense rim on FLAIR, consistent with a previous acute small subcortical infarct or haemorrhage in the territory of one perforating arteriole. Presence of lacunes was defined as the presence of one or more lacunes (1 point if present).
WMHs: signal abnormality of variable size in the white matter that exhibits the following characteristics: hyperintensity on T2-weighted images such as fluid-attenuated inversion recovery, without cavitation (signal different from CSF). The severity of periventricular WMH (PWMH) and deep WMH (DWMH) were both coded according to the Fazekas scale from 0 to 3. Presence of WMH was defined as either (early) confluent DWMH (Fazekas score 2 or 3) or irregular PWMH extending into the deep white matter (Fazekas score 3) (1 point if present) .
PVSs: small (<3 mm) punctate (if perpendicular) or linear (if longitudinal to the plane of scan) hyperintensities on T2 images in the basal ganglia. The severity of PVS was rated on a validated semiquantitative scale from 0 to 4 (0=no PVS; 1=<10 PVS; 2=11–20 PVS; 3=21–40 PVS; and 4=>40 PVS). The numbers refer to PVSs on one side of the brain; the higher score was used in case of asymmetry between the two sides. Presence of PVSs in the basal ganglia was counted if these were of moderate to severe (grade 2–4) (1 point if present) .
CMBs: small (generally 2–5 mm in diameter), homogeneous, round foci of low signal intensity on T2-weighted MRI or other sequences that are sensitive to susceptibility effects in the areas of cerebellum, brainstem, basal ganglia, white matter, or cortico-subcortical junction. Presence of CMBs was defined as the presence of any CMB (1 point if present).
PSG was recorded in a sleep laboratory for 2 consecutive nights and the average value of each parameter obtained on the 2 consecutive nights was calculated. Recording of PSG started based on the subject’s usual sleeping habits; each patient’s sleep was recorded for a minimum of 8 hours. The wireless telemetry polysomnography system (manufacturer: Germany SOMNOmedics; model: SOMNOscreen plus PSG +; analysis software "DOMINO") was used to monitor sleep. Sleep recordings were scored by a psychologist who was blinded to the group identity. All PSG records were staged and scored based on the American Academy of Sleep Medicine Manual . PSG measures reported included: sleep onset latency in minutes (SOL, the number of minutes it took for the participant to fall asleep after going to bed); total sleep time in minutes (TST, total minutes of sleep during the PSG recording); sleep efficiency % (SE %, total sleep time divided by time in bed); wake after sleep onset (WASO, the number of minutes being awake after initial sleep onset until last awakening); percentage of each sleep stage (N1, N2, N3 [slow wave sleep; SWS] and rapid eye movement [REM]); PLM in sleep index (PLMSI, the number of PLM/h); PLM arousal index (PLMAI, the number of PLM leading to arousal/h); apnea-hypopnea index (AHI, the mean number of apneas and hypopneas per hour of sleep. Score a respiratory event in adults as an apnea if both of the following are met: There is a drop in the peak signal excursion by ≥ 90% of pre-event baseline; The duration of the ≥ 90% drop in sensor signal is ≥ 10 seconds. Score a respiratory event as a hypopnea if all of the following are met: The peak signal excursions drop by ≥ 30% of pre-event baseline; The duration of the ≥ 30% drop in signal excursions is ≥ 10 seconds; There is ≥ 3% oxygen desaturation from pre-event base line or the event is associated with an arousal; arousal index (ArI, total number of episodes of arousal divided by the duration of sleep in hours. Electroencephalographic (EEG) arousal is defined as an abrupt shift in EEG frequency for 3–14 seconds, which may include theta, alpha and/or frequencies greater than 16Hz but not spindles). The ArI average score of the subjects in the control group was used as the cut-off value to define higher ArI in CSVD patients.
Pittsburgh sleep quality index (PSQI)-Chinese Version: The PSQI is a self-reported questionnaire used to assess the quality of sleep over the past one month. It contains seven domains including subjective sleep quality, sleep latency, sleep duration, sleep efficiency, and sleep disturbances, use of sleeping pills and daytime dysfunction. Each domain is scored on a scale of 0 to 3. The global PSQI score ranges from 0 to 21; a higher score indicates poorer sleep quality .
SPSS software package (version 20.0) was used for statistical analyses. Descriptive statistics are presented as mean ± standard deviation for normally-distributed continuous variables and as frequencies or proportions for categorical variables. The student’s t test was used to assess the between-group differences with respect to sleep parameters. Logistic regression was performed to evaluate the association between sleep fragmentation and CSVD imaging markers. Two-sided P-values ≤0.05 were considered indicative of statistical significance.