Moderate-Intensity Rosuvastatin Plus Ezetimibe Versus High-Intensity Rosuvastatin for Target Low-Density Lipoprotein Cholesterol Goal Achievement in Patients With Recent Ischemic Stroke: A Randomized Controlled Trial / 대한뇌졸중학회지

Background@#and Purpose Moderate-intensity statin plus ezetimibe versus high-intensity statin alone may provide a greater low-density lipoprotein cholesterol (LDL-C) reduction in patients with recent ischemic stroke. @*Methods@#This randomized, open-label, controlled trial assigned patients with recent ischemic stroke <90 days to rosuvastatin/ezetimibe 10/10 mg once daily (ROS10/EZT10) or to rosuvastatin 20 mg once daily (ROS20). The primary endpoint was LDL-C reduction ≥50% from baseline at 90 days. Key secondary endpoints were LDL-C <70 mg/dL and multiple lipid goal achievement, and composite of major vascular events. @*Results@#Of 584 randomized, 530 were included in the modified intention-to-treat analysis. The baseline LDL-C level was 130.2±34.7 mg/dL in the ROS10/EZT10 group and 131.0±33.9 mg/dL in the ROS20 group. The primary endpoint was achieved in 198 patients (72.5%) in the ROS10/EZT10 group and 148 (57.6%) in the ROS20 group (odds ratio [95% confidence interval], 1.944 [1.352–2.795]; P= 0.0003). LDL-C level <70 mg/dL was achieved in 80.2% and 65.4% in the ROS10/EZT10 and ROS20 groups (P=0.0001). Multiple lipid goal achievement rate was 71.1% and 53.7% in the ROS10/EZT10 and ROS20 groups (P<0.0001). Major vascular events occurred in 1 patient in the ROS10/EZT10 group and 9 in the ROS20 group (P=0.0091). The adverse event rates did not differ between the two groups. @*Conclusion@#Moderate-intensity rosuvastatin plus ezetimibe was superior to high-intensity rosuvastatin alone for intensive LDL-C reduction in patients with recent ischemic stroke. With the combination therapy, more than 70% of patients achieved LDL-C reduction ≥50% and 80% had an LDL-C <70 mg/dL at 90 days.

Stroke-Specific Predictors of Major Bleeding in Anticoagulated Patients With Stroke and Atrial Fibrillation: A Nationwide Multicenter Registry-Based Study

Background@#and Purpose The congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack (CHA2DS2-VASc) and hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol (HAS-BLED) scores have been validated in estimating the risks of ischemic stroke and major bleeding, respectively, in patients with atrial fibrillation (AF). This study investigated stroke-specific predictors of major bleeding in patients with stroke and AF who were taking oral anticoagulants (OACs). @*Methods@#Subjects were selected from patients enrolled in the Korean ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts (K-ATTENTION) nationwide multicenter registry between 2013 and 2015. Patients were excluded if they were not taking OACs, had no brain imaging data, or had intracranial bleeding directly related to the index stroke. Major bleeding was defined according to International Society of Thrombosis and Haemostasis criteria. Cox regression analyses were performed to assess the associations between clinical variables and major bleeding and Kaplan-Meier estimates were performed to analyze event-free survival. @*Results@#Of a total of 3,213 patients, 1,414 subjects (mean age of 72.6 years, 52.5% males) were enrolled in this study. Major bleeding was reported in 34 patients during the median follow-up period of 1.73 years. Multivariable analysis demonstrated that initial National Institutes of Health Stroke Scale scores (hazard ratio [HR] 1.07, p=0.006), hypertension (HR 3.18, p=0.030), persistent AF type (HR 2.51, p=0.016), and initial hemoglobin level (HR 0.74, p=0.001) were independently associated with major bleeding risk. Except for hypertension, these associations remained significant after adjusting for the HAS-BLED score. Intracranial atherosclerosis presented a trend of association without statistical significance (HR 2.21, p=0.050). @*Conclusions@#This study found that major bleeding risk was independently associated with stroke-specific factors in anticoagulated patients with stroke and AF. This has the clinical implication that baseline characteristics of patients with stroke and AF should be considered in secondary prevention, which would bring the net clinical benefit of balancing recurrent stroke prevention with minimal bleeding complications.

Wall Shear Stress Associated with Stroke Occurrence and Mechanisms in Middle Cerebral Artery Atherosclerosis / 대한뇌졸중학회지

Background@#and Purpose Various mechanisms are involved in the etiology of stroke caused by atherosclerosis of the middle cerebral artery (MCA). Here, we compared differences in plaque nature and hemodynamic parameters according to stroke mechanism in patients with MCA atherosclerosis. @*Methods@#Consecutive patients with asymptomatic and symptomatic MCA atherosclerosis (≥50% stenosis) were enrolled. MCA plaque characteristics (location and plaque enhancement) and wall shear stress (WSS) were measured using high-resolution vessel wall and four-dimensional flow magnetic resonance imaging, respectively, at five points (initial, upstream, minimal lumen, downstream, and terminal). These parameters were compared between patients with asymptomatic and symptomatic MCA atherosclerosis with infarctions of different mechanisms (artery-to-artery embolism vs. local branch occlusion). @*Results@#In total, 110 patients (46 asymptomatic, 32 artery-to-artery embolisms, and 32 local branch occlusions) were investigated. Plaques were evenly distributed in the MCA of patients with asymptomatic MCA atherosclerosis, more commonly observed in the distal MCA of patients with artery-to-artery embolism, and in the middle MCA of patients with local branch occlusion. Maximum WSS and plaque enhancement were more prominent in the minimum lumen area of patients with asymptomatic MCA atherosclerosis or those with local branch occlusion, and were more prominent in the upstream area in those with artery-to-artery embolism. The elevated variability in the maximum WSS was related to stroke caused by artery-to-artery embolism. @*Conclusion@#Stroke caused by artery-to-artery embolism was related to plaque enhancement and the highest maximum WSS at the upstream point of the plaque, and was associated with elevated variability of maximum WSS.

High-on-Aspirin Platelet Reactivity Differs Between Recurrent Ischemic Stroke Associated With Extracranial and Intracranial Atherosclerosis

Background@#and Purpose Ischemic stroke recurs despite the use of antiplatelet agents. Various mechanisms are involved in recurrence due to intracranial atherosclerosis (ICAS) and extracranial atherosclerosis (ECAS). High-on-aspirin platelet reactivity (HAPR) may differ between recurrent stroke due to ICAS and ECAS. @*Methods@#Patients with recurrent ischemic stroke as a result of large-artery atherosclerosis despite taking aspirin were enrolled consecutively. Ischemic stroke was classified as stroke due to ICAS or ECAS according to the location of the culprit stenosis. An aspirin reaction units (ARU) value of >550 IU was defined as HAPR. HAPR and its associated factors were compared between the two groups and also considering the mechanism of stroke. @*Results@#Among the 190 patients with recurrent stroke (111 with ICAS and 79 with ECAS), 36 (18.3%) showed HAPR. The ARU value was higher in the ECAS than the ICAS group (492± 83 vs. 465±78, mean±standard deviation; p=0.028), as was the proportion of patients with HAPR (27.8% vs. 12.6%, p=0.008). Being male and having stroke due to ECAS (reference = stroke due to ICAS: odds ratio=5.760; 95% confidence interval=2.154–15.403; p<0.001) was independently associated with HAPR. The ARU value differed according to the stroke mechanism, and was highest in those with artery-to-artery embolism. Artery-to-artery embolism was independently associated with HAPR in both the ICAS and ECAS groups. @*Conclusions@#Recurrent stroke due to ECAS was more strongly associated with HAPR and insufficient antiplatelet inhibition than was that due to ICAS. Artery-to-artery embolism was associated with HAPR in recurrent ischemic stroke as a result of ICAS or ECAS.

Initiation of Guideline-Matched Oral Anticoagulant in Atrial Fibrillation-Related Stroke / 대한뇌졸중학회지

Background@#and Purpose To evaluate the outcome events and bleeding complications of the European Society of Cardiology (ESC) guideline-matched oral anticoagulant therapy for patients with acute ischemic stroke and atrial fibrillation (AF). @*Methods@#Patients with acute ischemic stroke and AF from a nationwide multicenter registry (Korean ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts [K-ATTENTION]) between January 2013 and December 2015 were included in the study. Patients were divided into the ESC guideline-matched and the non-matched groups. The primary outcome was recurrence of any stroke during the 90-day follow-up period. Secondary outcomes were major adverse cerebrovascular and cardiovascular events, ischemic stroke, intracranial hemorrhage, acute coronary syndrome, allcause mortality, and major hemorrhage. Propensity score matching and logistic regression analyses were performed to assess the effect of the treatments administered. @*Results@#Among 2,321 eligible patients, 1,126 patients were 1:1 matched to the ESC guidelinematched and the non-matched groups. As compared with the non-matched group, the ESC guideline-matched group had a lower risk of any recurrent stroke (1.4% vs. 3.4%; odds ratio [OR], 0.41; 95% confidence interval [CI], 0.18 to 0.95). The risk of recurrent ischemic stroke was lower in the ESC guideline-matched group than in the non-matched group (0.9% vs. 2.7%; OR, 0.32; 95% CI, 0.11 to 0.88). There was no significant difference in the other secondary outcomes between the two groups. @*Conclusions@#ESC guideline-matched oral anticoagulant therapy was associated with reduced risks of any stroke and ischemic stroke as compared with the non-matched therapy.

Cerebral Artery Stenosis in a Young Stroke Patient with Eales’ Disease

Eales’ disease is an idiopathic disorder induced by ischemic retinal vasculitis, usually affecting the peripheral retina. We encountered a young patient diagnosed as cerebral infarction with a history of Eales’ disease. The patient’s middle cerebral artery showed multifocal stenosis with contrast enhancement, suggesting vasculitis. These findings might give clues to a rare cause of cerebral artery stenosis.

Changes in High-Density Lipoprotein Cholesterol and Risks of Cardiovascular Events: A Post Hoc Analysis from the PICASSO Trial / 대한뇌졸중학회지

Background@#and purpose Whether pharmacologically altered high-density lipoprotein cholesterol (HDL-C) affects the risk of cardiovascular events is unknown. Recently, we have reported the Prevention of Cardiovascular Events in Asian Patients with Ischaemic Stroke at High Risk of Cerebral Haemorrhage (PICASSO) trial that demonstrated the non-inferiority of cilostazol to aspirin and superiority of probucol to non-probucol for cardiovascular prevention in ischemic stroke patients (clinicaltrials.gov: NCT01013532). We aimed to determine whether on-treatment HDL-C changes by cilostazol and probucol influence the treatment effect of each study medication during the PICASSO study. @*Methods@#Of the 1,534 randomized patients, 1,373 (89.5%) with baseline cholesterol parameters were analyzed. Efficacy endpoint was the composite of stroke, myocardial infarction, and cardiovascular death. Cox proportional hazards regression analysis examined an interaction between the treatment effect and changes in HDL-C levels from randomization to 1 month for each study arm. @*Results@#One-month post-randomization mean HDL-C level was significantly higher in the cilostazol group than in the aspirin group (1.08 mmol/L vs. 1.00 mmol/L, P<0.001). The mean HDL-C level was significantly lower in the probucol group than in the non-probucol group (0.86 mmol/L vs. 1.22 mmol/L, P<0.001). These trends persisted throughout the study. In both study arms, no significant interaction was observed between HDL-C changes and the assigned treatment regarding the risk of the efficacy endpoint. @*Conclusions@#Despite significant HDL-C changes, the effects of cilostazol and probucol treatment on the risk of cardiovascular events were insignificant. Pharmacologically altered HDL-C levels may not be reliable prognostic markers for cardiovascular risk.

Causes, Risk Factors, and Clinical Outcomes of Stroke in Korean Young Adults: Systemic Lupus Erythematosus is Associated with Unfavorable Outcomes

Background@#and Purpose: The incidence of ischemic stroke (IS) in young adults is increasing, and the associated large socioeconomic impact makes understanding IS in young adults important. We investigated the causes of and risk factors for IS in young adults, and their impact on outcomes. @*Methods@#The Stroke in Korean Young Adults (SKY) study is a standardized multicenter prospective study involving eight medical centers of the Republic of Korea. First-ever IS patients aged 18 years to 44 years were prospectively included in this study within 7 days of stroke onset.Their outcomes at 3 months were analyzed. @*Results@#This study enrolled 270 patients from April 2014 to December 2018, most (67.8%) of whom were male. About 41.5% of the patients had one or more vascular risk factors from among hypertension, diabetes mellitus, and dyslipidemia. However, only half of them had received regular treatment. Arterial dissection was more common in males, and systemic lupus erythematosus (SLE) and Moyamoya disease were more common in females. The outcome was favorable (modified Rankin Scale score of 0 or 1) in 81.9% of the patients at 3 months after stroke onset. More severe initial symptoms, higher initial glucose level, and SLE as a comorbidity were associated with unfavorable outcomes. @*Conclusions@#Young adult IS patients in Korea exhibit low awareness and poor management of their risk factors. Although the short-term outcome was relatively favorable in those patients, having SLE was associated with unfavorable outcomes. More attention needs to be paid for improving awareness and controlling risk factors in this population.

Clinical Characteristics of Non-Amnestic Mild Cognitive Impairment: A Single-Center Experience

BACKGROUND: To evaluate the clinical characteristics of patients with non-amnestic mild cognitive impairment (naMCI) in a memory disorder clinic at a single center. METHODS: A retrospective study was conducted involving 312 patients with naMCI from May 2011 to July 2018. Brain magnetic resonance imaging and detailed neuropsychological tests were performed in all patients. We used the proposed criteria for naMCI to classify the patients into single- and multiple-domain groups. We compared the baseline clinical characteristics, neuroimaging findings, and the rate of progression to dementia between these two groups. RESULTS: The 312 patients comprised 210 in the single-domain group (67.3%) and 102 in the multiple-domain group (32.7%). The mean age was significantly higher in the multiple-domain group than in the single-domain group. The years of education, mean Mini Mental State Examination score, and mean Clinical Dementia Rating Scale Sum of Boxes score were significantly lower in the multiple-domain group than in the single-domain group. The Z-scores of neuropsychological tests in most cognitive domains were significantly lower in the multiple-domain group than in the single-domain group. Compared to the single-domain group, the multiple-domain group showed more-severe medial temporal atrophy and contained a higher proportion of patients with moderate white-matter hyperintensities. Thirteen (8.4%) patients with naMCI progressed to dementia, most of who were diagnosed with Alzheimer's disease. CONCLUSIONS: We present a single-center experience of clinical characteristics in patients with naMCI. Close observation of the clinical profiles of patients with naMCI may help identify individuals at the greatest risk of dementia.

Ischemic Stroke after Overdose of Oral Quetiapine

No abstract available.

Long-Term Outcomes of Real-World Korean Patients with Atrial-Fibrillation-Related Stroke and Severely Decreased Ejection Fraction

BACKGROUND AND PURPOSE: The clinical implications of echocardiography findings for long-term outcomes in atrial fibrillation (AF)-related stroke patients are unknown. METHODS: This was a substudy of the Korean ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts (K-ATTENTION), which is a multicenter-based cohort comprising prospective stroke registries from 11 tertiary centers. Stroke survivors who underwent two-dimensional transthoracic echocardiography during hospitalization were enrolled. Echocardiography markers included the left-ventricle (LV) ejection fraction (LVEF), the left atrium diameter, and the ratio of the peak transmitral filling velocity to the mean mitral annular velocity during early diastole (E/e′ ratio). LVEF was categorized into normal (≥55%), mildly decreased (>40% and <55%), and severely decreased (≤40%). The E/e′ ratio associated with the LV filling pressure was categorized into normal (<8), borderline (≥8 and <15), and elevated (≥15). Kaplan-Meier and Cox regression analyses were performed for recurrent stroke, major adverse cardiac events, and all-cause death. RESULTS: This study finally included 1,947 patients. Over a median follow-up of 1.65 years (interquartile range, 0.42–2.87 years), the rates of recurrent stroke, major adverse cardiac events, and all-cause death were 35.1, 10.8, and 69.6 cases per 1,000 person-years, respectively. Multivariable analyses demonstrated that severely decreased LVEF was associated with a higher risks of major adverse cardiac events [hazard ratio (HR), 3.91; 95% confidence interval (CI), 1.58–9.69] and all-cause death (HR, 1.95; 95% CI, 1.23–3.10). The multivariable fractional polynomial plot indicated that recurrent stroke might be associated with a lower LVEF. CONCLUSIONS: Severe LV systolic dysfunction could be a determinant of long-term outcomes in AF-related stroke.

Differences between the Molecular Mechanisms Underlying Ruptured and Non-Ruptured Carotid Plaques, and the Significance of ABCA1 / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: Carotid plaques are a strong risk factor for ischemic stroke, and plaque rupture poses an even higher risk. Although many studies have investigated the pathogenic mechanisms of carotid plaque formation, few have studied the differences in molecular mechanisms underlying the rupture and non-rupture of carotid plaques. In addition, since early diagnosis and treatment of carotid plaque rupture are critical for the prevention of ischemic stroke, many studies have sought to identify the important target molecules involved in the rupture. However, a target molecule critical in symptomatic ruptured plaques is yet to be identified. METHODS: A total of 79 carotid plaques were consecutively collected, and microscopically divided into ruptured and non-ruptured groups. Quantitative polymerase chain reaction array, proteomics, and immunohistochemistry were performed to compare the differences in molecular mechanisms between ruptured and non-ruptured plaques. Enzyme-linked immunosorbent assay was used to measure the differences in ATP-binding cassette subfamily A member 1 (ABCA1) levels in the serum. RESULTS: The expression of several mRNAs and proteins, including ABCA1, was higher in ruptured plaques than non-ruptured plaques. In contrast, the expression of other proteins, including β-actin, was lower in ruptured plaques than non-ruptured plaques. The increased expression of ABCA1 was consistent across several experiments, ABCA1 was positive only in the serum of patients with symptomatic ruptured plaques. CONCLUSIONS: This study introduces a plausible molecular mechanism underlying carotid plaque rupture, suggesting that ABCA1 plays a role in symptomatic rupture. Further study of ABCA1 is needed to confirm this hypothesis.

Basilar Artery Plaque and Pontine Infarction Location and Vascular Geometry / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: Subclinical atherosclerotic plaques are common in patients with pontine infarctions (PIs) but without basilar artery (BA) stenosis. We hypothesized that BA plaque locations may differ by PI type and vertical location as well as vertebrobasilar artery geometry. METHODS: Ninety-six patients with PI but without BA stenosis on magnetic resonance imaging (MRI) and magnetic resonance angiography were enrolled. PIs were classified by type (paramedian, deep, or lateral) and vertical location (rostral, middle, or caudal). Patients underwent high-resolution MRI to evaluate BA plaque location (anterior, posterior, or lateral). The mid-BA angle on anteroposterior view and angle between the BA and dominant vertebral artery (BA-VA angle) on lateral view were measured. RESULTS: The PIs were paramedian (72.9%), deep (17.7%), and lateral (9.4%) type with a rostral (32.3%), middle (42.7%), and caudal (25.0%) vertical location. The BA plaque locations differed by PI type (P=0.03) and vertical location (P < 0.001); BA plaques were most frequent at the posterior wall in paramedian (37.1%) and caudal (58.3%) PIs and at the lateral wall in lateral (55.5%) and middle (34.1%) PIs. The BA-VA and mid-BA angles differed by BA plaque and PI vertical location; the greatest BA-VA angle was observed in patients with posterior plaques (P < 0.001) and caudal PIs (P<0.001). Greatest mid-BA angles were observed with lateral BA plaques (P=0.03) and middlelocated PIs (P=0.03). CONCLUSIONS: Greater mid-BA angulation may enhance lateral plaque formation, causing lateral and middle PIs, whereas greater BA-VA angulation may enhance posterior plaque formation, causing paramedian or caudal PIs.

Ethnic Differences in Intracranial Artery Tortuosity: A Possible Reason for Different Locations of Cerebral Atherosclerosis / 대한뇌졸중학회지

No abstract available.

Syndrome of inappropriate antidiuretic hormone secretion associated with seronegative neuromyelitis optica spectrum disorder

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a potential cause of hyponatremia of the central nervous system (CNS). Although SIADH has been reported to be associated with many other central nervous disorders, its association with neuromyelitis optica (NMO) or NMO spectrum disorders are rare. NMO is a demyelinating disorder characterized by optic neuritis and transverse myelitis. Aquaporin-4 (AQP4), which is the target antigen for a NMO autoantibody, is the predominant CNS water channel. However, some NMO patients show seronegative AQP4 antibody results. The spectrum of NMO has been changed, and new findings about the disease have been reported. Here, we report a case of seronegative NMO spectrum disorder associated with SIADH.

Different Clinical Courses of Idiopathic Isolated Hypoglossal Nerve Palsy / 대한임상신경생리학회지

No abstract available.

Preoperative Coronary Stenosis Is a Determinant of Early Vascular Outcome after Carotid Endarterectomy

BACKGROUND AND PURPOSE: The benefit of carotid endarterectomy (CEA) is directly influenced by the risk of perioperative adverse outcomes. However, patient-level risks and predictors including coronary stenosis are rarely evaluated, especially in Asian patients. The aim of this study was to determine the relationship between the vascular risk factors underlying CEA, including coronary stenosis, and postoperative outcome. METHODS: One hundred and fifty-three consecutive CEAs from our hospital records were included in this analysis. All patients underwent coronary computed tomography angiography before CEA. Data were analyzed to determine the vascular outcomes in patients with mild-to-moderate vs. severe coronary stenosis and high vs. standard operative risk, based on the criteria for high operative risk defined in the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. The vascular outcome was defined as the occurrence of postoperative (< or =30 days) stroke, myocardial infarction (MI), or death. RESULTS: An adverse vascular outcome occurred in 8 of the 153 CEAs, with 6 strokes, 2 MIs, and 3 deaths. The vascular outcome differed significantly between the groups with mild-to-moderate and severe coronary stenosis (p=0.024), but not between the high- and standard-operative-risk groups (stratified according to operative risk as defined in the SAPPHIRE trial). Multivariable analysis adjusting for potent predictors revealed that severe coronary stenosis (odds ratio, 6.87; 95% confidence interval, 1.20-39.22) was a significant predictor of the early vascular outcome. CONCLUSIONS: Severe coronary stenosis was identified herein as an independent predictor of an adverse early vascular outcome.

Early-stage Alcoholic Cerebellar Degeneration: Diagnostic Imaging Clues

No abstract available.

Impairments of Inhibitory Motor Control in Cerebral Cortical Infarction

No abstract available.

Sleep Disturbances and Predictive Factors in Caregivers of Patients with Mild Cognitive Impairment and Dementia

BACKGROUND AND PURPOSE: We examined the characteristics of sleep disturbances and sleep patterns in the caregivers of patients with amnestic mild cognitive impairment (aMCI) and dementia. METHODS: We prospectively studied 132 patients (60 with aMCI and 72 with dementia) and their caregivers, and 52 noncaregiver controls. All caregivers and controls completed several sleep questionnaires, including the Pittsburgh Sleep Quality Index (PSQI). The patients were administered neuropsychological tests and the neuropsychiatric inventory to evaluate their behavioral and neuropsychiatric symptoms of dementia (BPSD). RESULTS: The PSQI global score was 6.25+/-3.88 (mean+/-SD) for the dementia caregivers and 5.47+/-3.53 for the aMCI caregivers. The Insomnia Severity Index (ISI) and short form of the Geriatric Depression Scale (GDS-S) predicted higher PSQI global scores in aMCI caregivers, and higher scores for the ISI, Epworth Sleepiness Scale (ESS), and GDS-S in dementia caregivers. BPSD, including not only agitation, depression, and appetite change in dementia patients, but also depression, apathy, and disinhibition in aMCI patients, was related to impaired sleep quality of caregivers, but nighttime behavior was not. Age and gender were not risk factors for disturbed sleep quality. CONCLUSIONS: Dementia and aMCI caregivers exhibit impaired quality of sleep versus non-caregivers. ISI, GDS-S, and ESS scores are strong indicators of poor sleep in dementia caregivers. In addition, some BPSD and parts of the neuropsychological tests may be predictive factors of sleep disturbance in dementia caregivers.