Age-related white matter changes are common in the elderly and are considered as manifestation of arteriolosclerotic small vessel disease. Most recent studies have shown that the white matter changes are associated with cognitive impairment and dementia, urinary incontinence, gait disturbances, depression and increased risk of stroke and death. Although the clinical phenotypes of the white matter changes have been extensively studied, to date, only few clinical trials have been conducted in this area. In this review, we discussed the current understanding in the epidemiology, pathogenesis, imaging features, chemical biomarkers, clinical importance, and management of age-related white matter changes, with special emphasis in studies that were conducted among Asians.

OBJECTIVE: To evaluated whether clusterin over-expression is significantly correlated with paclitaxel resistance in ovarian cancer cell lines. METHODS: Clusterin was validated by performing expression profiling analysis and subsequently, the correlation between clusterin mRNA expression levels and the IC50 of paclitaxel was tested. Transfection of clusterin was performed on SKOV3, which expressed paclitaxel-sensitivity and low level of clusterin, and transfection of clusterin siRNA on PEOH, which expressed paclitaxel-resistance and high level of clusterin, to evaluate their effect on chemo-sensitivity, apoptosis, and cell cycle by XTT assay, cell death ELISA, and flow cytometry, respectively. RESULTS: Clusterin mRNA and protein expression levels were significantly correlated with paclitaxel resistance (P<0.001). Transfection of cluterin on SKOV3 significantly decreased apoptosis and increased paclitaxel resistance. And transfection of clusterin siRNA on PEOH significantly increased paclitaxel-sensitivity (P<0.05), and shifted cells from S to G2/M phase of the cell cycle after paclitaxel treatment. CONCLUSION: These findings suggested that clusterin overexpression confers paclitaxel-resistance by the modulation of the apoptotic pathway and cell cycle progression in ovarian cancer cells.
Apoptosis ; Cell Cycle ; Cell Death ; Cell Line ; Clusterin* ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Inhibitory Concentration 50 ; Ovarian Neoplasms* ; Paclitaxel* ; RNA, Messenger ; RNA, Small Interfering ; Transfection

Lacunar infarcts/lacunes, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs) are considered various manifestations of cerebral small vessel disease (SVD). Since the exact mechanisms of these manifestations differ, their associated risk factors differ. High blood pressure is the most consistent risk factor for all of these manifestations. However, a "J curve" phenomenon in terms of blood pressure probably exists for WMH. The association between cholesterol levels and lacunar infarcts/lacunes or WMH was less consistent and sometimes conflicting; a low cholesterol level probably increases the risk of CMBs. Homocysteinemia appears to be associated with WMH. It is noteworthy that the risk factors profile may also differ between different lacunar patterns and CMBs located at different parts of the brain. Thrombolysis, antihypertensives, and statins are used to treat patients with symptomatic lacunar infarction, just as in those with other stroke subtypes. However, it should be remembered that bleeding risks increase in patients with extensive WMH and CMBs after thrombolysis therapy. According to the Secondary Prevention of Small Subcortical Strokes trial results, a blood pressure reduction to <130 mmHg is recommended in patients with symptomatic lacunar infarction. However, an excessive blood pressure decrease may induce cognitive decline in older patients with extensive WMH. Dual antiplatelet therapy (aspirin plus clopidogrel) should be avoided because of the excessive risk of intracerebral hemorrhage. Although no particular antiplatelet is recommended, drugs such as cilostazol or triflusal may have advantages for patients with SVD since they are associated with less frequent bleeding complications than aspirin.
Antihypertensive Agents ; Aspirin ; Blood Pressure ; Brain ; Cerebral Hemorrhage ; Cerebral Small Vessel Diseases* ; Cholesterol ; Hemorrhage ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Hypertension ; Risk Factors ; Secondary Prevention ; Stroke ; Stroke, Lacunar

Objectives: Intracranial atherosclerosis, especially the middle cerebral artery (MCA), is the commonestvascular lesion for ischemic stroke the Chinese population. We explored the association of geneticpolymorphism and environmental factors in MCA atherosclerosis in the Chinese population. Methods:One hundred fifty-six ischemic stroke patients with MCA stenosis and 181 well-matched ischemicstroke patients without MCA stenosis were examined by polymerase chain reaction (PCR). ThePCR products were analyzed for lipoprotein lipase (LPL) S447X and paraoxonase1 (PON1) Q192Rpolymorphisms by restriction enzyme digestion. Medical history documentation and investigationof biochemical markers were performed for each subject. Results: Univariate analysis showed thatthe levels of systolic blood pressure (SBP) were higher in the MCA stenosis group. There were nosignificant differences in the genotype and allele frequencies of the LPL S447X and PON1 Q192Rpolymorphism observed between the two groups. But, in the patients above 60 years of age with andwithout MCA stenosis, LPL X carriers have higher level of SBP than the LPL SS genotype carriers.Multivariate logistic regression found that SBP was the significant, independent predictor of thepresence of MCA stenosis patients above 60 years of age (P < 0.001, OR=1.206, 95% confidenceintervals: 1.014-1.032).Conclusions: SBP appears to contribute to the pathogenesis of MCA stenosis among Chinese. Thegene polymorphism of LPL S447X may be associated with atherosclerotic MCA stenosis in Chinesepopulation.

Background: and Purpose Paroxysmal atrial fibrillation (PAF) underlying acute stroke frequently evades detection by standard practice, considered to be a combination of routine electrocardiogram (ECG) monitoring, and 24-hour Holter recordings. We hypothesized that nurse-led in-hospital intermittent monitoring approach would increase PAF detection rate. Methods: We recruited patients hospitalised for stroke/transient ischemic attack, without history of atrial fibrillation (AF), in a prospective multi-centre observational study. Patients were monitored using a smartphone-enabled handheld ECG (iECG) during routine nursing observations, and underwent 24-hour Holter monitoring according to local practice. The primary outcome was comparison of AF detection by nurse-led iECG versus Holter monitoring in patients who received both tests: secondary outcome was oral anticoagulant commencement at 3-month following PAF detection. Results: One thousand and seventy-nine patients underwent iECG monitoring: 294 had iECG and Holter monitoring. AF was detected in 25/294 (8.5%) by iECG, and 8/294 (2.8%) by 24-hour Holter recordings (P<0.001). Median duration from stroke onset to AF detection for iECG was 3 days (interquartile range [IQR], 2 to 6) compared with 7 days (IQR, 6 to 10) for Holter recordings (P=0.02). Of 25 patients with AF detected by iECG, 11 were commenced on oral anticoagulant, compared to 5/8 for Holter. AF was detected in 8.8% (69/785 patients) who underwent iECG recordings only (P=0.8 vs. those who had both iECG and 24-hour Holter). Conclusions Nurse-led in-hospital iECG surveillance after stroke is feasible and effective and detects more PAF earlier and more frequently than routine 24-hour Holter recordings. Screening with iECG could be incorporated into routine post-stroke nursing observations to increase diagnosis of PAF, and facilitate institution of guideline-recommended anticoagulation.

No abstract available.
Hong Kong* ; Rehabilitation* ; Stroke*

Objective: Data on early-onset dementia in Chinese is limited. This study aimed to report the diagnostic profiles and characteristics of patients with early-onset dementia in a university-affiliated cognitive disorder clinic in Hong Kong. Methods: We prospectively collected data of consecutive patients who were referred between January 2012 and December 2018. All patients were referred for diagnostic evaluation of cognitive symptoms. Patients with symptom-onset at age 65 or before were recruited. We excluded patients with (1) cognitive deficits referable to an isolated event or toxin and (2) significant mood disorders. Results: Of the 93 patients included, four patients had temporal lobe epilepsy mimicking dementia. Three patients had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), one patient had Niemann-Pick disease type C and two patients had undetermined aetiology. The remaining 83 patients had primary degenerative dementia. The most frequent diagnosis wasAlzheimer’s disease (AD) (70%), followed by frontotemporal dementia (FTD) (22%) and parkinsonian disorders (8%). The mean age of symptom onset was 57.8 ± 5.8 years.Ten (17%) AD patients had non-amnestic presentation. Fifteen FTD patients consented for mutation screening in the GRN (progranulin), MAPT (microtubule-associated protein tau) and C9orf72 genes, none were positive. Conclusions: Early-onset dementia had a broader differential diagnoses than late-onset dementia, and includes a number of rare hereditary diseases. Patients with suspected early-onset dementia should be thoroughly evaluated to identify any treatable causes.

The common cerebral small vessel disease (CSVD) neuroimaging features visible on conventional structural magnetic resonance imaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. The CSVD neuroimaging features have shared and distinct clinical consequences, and the automatic quantification methods for these features are increasingly used in research and clinical settings. This review article explores the recent progress in CSVD neuroimaging feature quantification and provides an overview of the clinical consequences of these CSVD features as well as the possibilities of using these features as endpoints in clinical trials. The added value of CSVD neuroimaging quantification is also discussed for researches focused on the mechanism of CSVD and the prognosis in subjects with CSVD.
Cerebral Small Vessel Diseases/diagnostic imaging* ; Humans ; Magnetic Resonance Imaging ; Neuroimaging ; Prognosis

Age-related sporadic cerebral small vessel disease (CSVD) has gained increasing attention over the past decades because of its increasing prevalence associated with an aging population. The widespread application of and advances in brain magnetic resonance imaging in recent decades have significantly increased researchers' understanding in the in vivo evolution of CSVD, its impact upon the brain, its risk factors, and the mechanisms that explain the various clinical manifestation associated with sporadic CSVD. In this review, we aimed to provide an update on the pathophysiology, risk factors, biomarkers, and the determinants and spectrum of the clinical manifestation of sporadic CSVD.
Aged ; Aging ; Brain/diagnostic imaging* ; Cerebral Small Vessel Diseases/epidemiology* ; Humans ; Magnetic Resonance Imaging ; Pandemics

Positive-sense RNA viruses modify intracellular calcium stores, endoplasmic reticulum and Golgi apparatus (Golgi) to generate membranous replication organelles known as viral factories. Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity. Here, we identified the vital role of a broad-spectrum antiviral, peruvoside in limiting the formation of viral factories. Mechanistically, we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) phosphorylation and Golgi vesiculation by peruvoside treatment. The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation. Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337 (T1337). We also showed 100% of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum. These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside, host-directed antivirals for positive-sense RNA virus-mediated disease, in the interim where no vaccine is available.