Design:This was a cross-sectional case-control study in a single-center. The CSVD patients were consecutively recruited from outpatient clinics of the Third Affiliated Hospital of Sun Yat-sen University from September 2017 to December 2018. The healthy control group was the healthy spouse or sibling of the CSVD patients.
Participants
A total group of 84 CSVD patients were recruited following the inclusion/exclusion criteria, along with 24 normal controls matched with sex and age. All participants underwent structured interviews and physical examination by a study physician who confirmed the diagnosis.
Inclusion criteria:
- Age 50–70 y.
- Had at least one of the following vascular risk factors: hypertension, atherosclerosis, diabetes mellitus, past or current smoking.
- Had 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.
- Presenting with evidence of one or more MR markers of CSVD [11]: lacunars, WMHs with Fazekas grade 2(early confluent) or higher [12], visible PVSs and cerebral microbleeds (CMBs).
- Controls without vascular risk factors, CSVD symptoms and MR marks of CSVD.
- Signed the written informed consent form.
Exclusion criteria
- With larger subcortical or cerebral Water-shed infarctions (>1.5 cm) on MR as these are often embolic.
- With large artery disease-carotid, vertebral or intracranial stenosis >50%;
- With severe mental disorders such as schizophrenia, bipolar disorder or major depression, alcohol and/or other drug abuse or dependence;
- With uncontrolled somatic disorders or sleep-disruptive comorbid medical condition (e.g., moderate to severe rheumatoid arthritis); needed immediate psychiatric (e.g., imminently suicidal patients) or medical care (e.g., patients with acute cardiac symptoms)
- With breathing-related sleep disorders, restless legs syndrome, or circadian rhythm sleep disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [13].
- Apnea-hypopnea index ≥15 or/and periodic limb movement-related arousal index ≥15 per hour of sleep during a screening laboratory polysomnogram;
- Patients with CSVD caused by other reasons such as hereditary, inflammatory and amyloidosis.
- Being treated with medications that affect sleep within two weeks of initial screening.
- 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 model for the presence of four CSVD makers as shown in the followings; the presence of each SVD makers was summed in an ordinal “SVD burden score” (range 0–4) [14].
Lacunes: rounded or ovoid lesions, >3- and <15-mm diameter, in the basal ganglia, internal capsule, centrum semiovale, or brainstem, of CSF signal intensity 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 shows 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) [12].
PVSs: small (<3 mm) punctate (if perpendicular) and linear (if longitudinal to the plane of scan) hyperintensities on T2 images in the basal ganglia, and the severity of PVS was rated on a validated semiquantitative scale from 0 to 4(0 = no PVS, 1 = <10 PVS, 2 = 11 to 20 PVS, 3 = 21 to 40 PVS, and 4 = >40 PVS). The numbers refer to PVSs on one side of the brain; the higher score was used if there was asymmetry between the two sides. Presence of PVSs was counted if there were moderate to severe (grade 2–4) PVSs in the basal ganglia (1 point if present) [15].
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:
PSG was recorded in a sleep laboratory and readings were averaged over 2 consecutive nights. Recording of PSG started based on the subject’s usual sleeping habits and each patient’ sleep was recorded for a minimum of 8 hours. The wireless telemetry polysomnography system (manufacturer: Germany SOMNOmedics,product model: SOMNOscreen plus PSG +, analysis software “DOMINO”) was used to monitor sleep. Sleep recordings were scored by a psychologist blinded to the group assignment. All PSG records were staged and scored based on the American Academy of Sleep Medicine Manual[16].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 RNEM),apnea-hypopnea index (AHI, % time oxygen saturation < 90%), arousal index (ArI; total number of arousal divided by the duration of sleep in hours), The cutoff value for higher ArI in CSVD patients was defined as the ArI average score of the participants in control group.
Pittsburgh sleep quality index(PSQI)-Chinese Version: The PSQI is a self-reported questionnaire to assess the quality of sleep over the past 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 scores from 0 to 3, yielding a global PSQI score ranging from 0 to 21, where a higher score indicates poorer sleep quality [17].
Statistical methods:
SPSS software package (version 20.0) was used for the statistical analyses. Descriptive statistics were presented as mean ± standard deviations for continuous normal variables and as numbers or proportions for categorical variables. The student’s t test was used for the comparison of sleep parameters between the study and control group. Logistic regression was performed to evaluate the association between sleep fragmentation and CSVD imaging markers. Two-sided P-values were considered to be statistically significant at ≤0.05.