Yunyun Xiong

Age-related white matter changes.

Age-related white matter changes (WMC) are considered manifestation of arteriolosclerotic small vessel disease and are related to age and vascular risk factors. Most recent studies have shown that WMC are associated with a host of poor outcomes, including cognitive impairment, dementia, urinary incontinence, gait disturbances, depression, and increased risk of stroke and death. Although the clinical relevance of WMC has been extensively studied, to date, only very few clinical trials have evaluated potential symptomatic or preventive treatments for WMC. In this paper, we reviewed the current understanding in the pathophysiology, epidemiology, clinical importance, chemical biomarkers, and treatments of age-related WMC.

Risk factors for incident dementia after stroke and transient ischemic attack

We hypothesized that chronic brain changes are important substrates for incident dementia after stroke and transient ischemic attack (TIA).

B Vitamins and Magnetic Resonance Imaging–Detected Ischemic Brain Lesions in Patients With Recent Transient Ischemic Attack or Stroke The VITAmins TO Prevent Stroke (VITATOPS) MRI-Substudy

Background and Purpose— Elevated concentrations of homocysteine are associated with cerebral small vessel disease (CSVD). b-vitamin supplementation with folate and vitamins b12 and b6 reduces homocysteine concentrations. In a substudy of the VITAmins TO Prevent Stroke (VITATOPS) trial, we assessed the hypothesis that the addition of once-daily supplements of b vitamins would reduce the progression of CSVD-related brain lesions. Methods— A total of 359 patients with recent stroke or transient ischemic attack, who were randomly allocated to double-blind treatment with placebo or b vitamins, underwent brain MRI at randomization and after 2 years of b-vitamin supplementation. MR images were analyzed blinded to treatment allocation. Outcomes related to the prespecified hypothesis were progression of white matter hyperintensities and incident lacunes. We also explored the effect of b-vitamin supplementation on the incidence of other ischemic abnormalities. Results— After 2 years of treatment with b vitamins or placebo, there was no significant difference in white matter hyperintensities volume change (0.08 vs 0.13cm3; P=0.419) and incidence of lacunes (8.0% vs 5.9%, P=0.434; odds ratio=1.38). In a subanalysis of patients with MRI evidence of severe CSVD at baseline, b-vitamin supplementation was associated with a significant reduction in white matter hyperintensities volume change (0.3 vs 1.7cm3; P=0.039). Conclusions— Daily b-vitamin supplementation for 2 years did not significantly reduce the progression of brain lesions resulting from presumed CSVD in all patients with recent stroke or transient ischemic attack but may do so in the subgroup of patients with recent stroke or transient ischemic attack and severe CSVD. Clinical Trial Registration— http://vitatops.highway1.com.au/. Unique identifier: NCT00097669 and ISRCTN74743444.

Transcranial Doppler Ultrasound for Screening Cerebral Small Vessel Disease A Community Study

Background and Purpose— We explored the association between pulsatility index (PI) as derived from transcranial Doppler ultrasound with various measures of small vessel disease in the community. Methods— We performed transcranial Doppler and magnetic resonance imaging in 205 consecutive community-dwelling elderly subjects who were participants of the Shanghai Aging Study. We investigated the association between middle cerebral artery (MCA) PI with measures of white matter lesions (WML), lacunes, and microbleeds. Results— Multiple logistic regression found that MCA PI was associated with severe WML (odds ratio, 1.33 per 0.1 increase in PI; 95% confidence interval, 1.04–1.70; P=0.02). At optimal MCA PI cut-off, the area under curve, positive predictive value, and negative predictive value were 0.70 (95% confidence interval, 0.60–0.80), 34.9%, and 85.6%, respectively, for detection of severe WML. No association was found between MCA PI and measures of lacunes or microbleeds. Conclusions— PI correlates with WML severity. With a high negative predictive value, the chance of having severe WML with a normal PI is low. Transcranial Doppler may guide selective magnetic resonance imaging scanning for the detection of WML in the community.

Cortical and frontal atrophy are associated with cognitive impairment in age-related confluent white-matter lesion

Objective Although age-related confluent white-matter lesion (WML) is an important substrate for cognitive impairment, the mechanisms whereby WML induces cognitive impairment are uncertain. The authors investigated cognitive predictors in patients with confluent WML. Methods Among 100 patients with ischaemic stroke with confluent WML on MRI, the authors assessed executive function and global cognition by the Mattis Dementia Rating Scale—Initiation/Perseveration Subscale (MDRS I/P) and Mini-Mental State Examination (MMSE), respectively. All volumetric measures were corrected for intracranial volume. The authors investigated the association between basic demography, vascular risk factors, APOE status, WML volume, infarct measures (volume, number, location), microbleed number, atrophy measures (global, central, regional) and cognitive performance. The authors also performed Pittsburgh Compound B (PIB) imaging among seven cognitive impaired patients with stroke. Results WML was no longer related to cognitive performance after adding atrophy into regression equations. Multivariate regression models showed that cortical grey matter volume independently accounted for performance on both the MDRS I/P (β=0.241, p=0.045) and MMSE (β=0.243, p=0.032). Models examining frontal subregions revealed that volumes of both left (β=0.424, p<0.001) and right (β=0.219, p=0.045) lateral frontal orbital gyri predicted MDRS I/P, whereas education (β=0.385, p<0.001) and left lateral frontal orbital gyrus (β=0.222, p=0.037) predicted MMSE. Volumes of WML and cognitively relevant brain regions were significantly associated. Seven patients with PIB imaging showed no uptake pattern typical of Alzheimers disease, suggesting a predominantly vascular aetiology for the cognitive impairment and brain changes in these patients. Conclusions Cognitive impairment in patients with confluent WML is mediated by global and frontal cortical atrophy.

Pittsburgh compound B binding in poststroke dementia

We hypothesize that Pittsburgh compound B (PIB) binding is common in poststroke dementia (PSD) and that cognitive decline may be faster in PIB positive patients. We performed PIB positron emission tomography (PET) among 17 subjects: 10 PSD patients, 4 Alzheimers disease (AD) patients, and 3 healthy controls. We also compared the rate of change in mini-mental state examination (MMSE) between PIB positive and negative patients. We detected AD-like PIB binding in 4 PSD patients (40%), all the AD patients, and 1 healthy control. The global PIB retention standardized uptake value (SUV) at 35-45 min for PIB positive stroke patients was 1.67 (range 1.56-1.82), which was similar to the AD patients (1.65; range 1.46-1.88) and was lower than PIB negative patients (1.29, range 1.24-1.34). Mean annual MMSE decline for the 4 PIB positive patients was 2.9 and that for the 6 PIB negative patients was 1. This pilot study suggests that PIB PET is feasible for the evaluation of PSD and PIB binding may be common in PSD. Whether presence of PIB binding is associated with a more rapid cognitive decline in PSD requires further study to confirm.

Deep brain stimulation.

Deep brain stimulation (DBS) has provided remarkable therapeutic benefits for people with a variety of neurological disorders. Despite the uncertainty of the precise mechanisms underlying its efficacy, DBS is clinically effective in improving motor function of essential tremor, Parkinsons disease and primary dystonia and in relieving obsessive-compulsive disorder. Recently, this surgical technique has continued to expand to other numerous neurological diseases with encouraging results. This review highlighted the current and potential future clinical applications of DBS.

Impacts and interactions of PDGFRB, MMP-3, TIMP-2, and RNF213 polymorphisms on the risk of Moyamoya disease in Han Chinese human subjects

Polymorphisms of PDGFRB, MMP-3, TIMP-2, RNF213, TGFB1, Raptor and eNOS genes have been associated with Moyamoya disease (MMD) separately in studies, but their interactions on MMD have never been evaluated in one study. This study enrolled 96 MMD patients and 96 controls to evaluate the contributions and interactions of these polymorphisms on MMD in Chinese Hans. After genotyping, five polymorphisms loci were deemed suitable for analysis, rs3828610 in PDGFRB, rs3025058 in MMP-3, rs8179090 in TIMP-2, rs112735431 and rs148731719 in RNF213. Interactions of different loci on MMD were evaluated by multifactor dimensionality reduction (MDR) method. Significantly higher frequencies of A allele and G/A genotype of rs112735431 in RNF213 were observed in MMD patients compared with controls (P=0.011; P=0.018, respectively). In the dominant model, G/A genotype of rs112735431 was associated with increased risk of MMD (P=0.018). A higher frequency of G allele and G/G genotype of rs148731719 in RNF213 gene in patient than control group (P<0.001; P<0.01, respectively) was also detected. No significant association between MMD and other three loci (P>0.05) was detected. MDR analysis failed to detect any significant interaction among these five loci in the occurrence of MMD (P>0.05), but the combination of three loci (rs112735431 in RNF213, rs3828610 in PDGFRB, rs3025058 in MMP-3) could have the maximum testing accuracy (57.29%) and cross-validation consistency (10/10). The results indicated that RNF213 rs112735431 and rs148731719 may exert a significant influence on MMD occurrence. Compared with this overwhelming effect, the influences of PDGFRB, MMP-3, and TIMP-2 on MMD may be unremarkable in Chinese Hans. There may be no prominent interaction among these five gene polymorphisms on the occurrence of MMD.

Chronic Kidney Disease in Patients With Lacunar Stroke Association With Enlarged Perivascular Spaces and Total Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease

Background and Purpose— The relationship between chronic kidney disease and cerebral small vessel disease (cSVD), especially enlarged perivascular spaces (EPVS), has not been fully understood. This study aimed to investigate the association of chronic kidney disease and EPVS, as well as the total burden of cSVD on magnetic resonance imaging, expressed by the simultaneous presence of multiple markers of cSVD, among patients with first-ever lacunar stroke. Methods— Four hundred and thirteen consecutive patients were prospectively enrolled. Centrum semiovale and basal ganglia EPVS on T2-weighted magnetic resonance imaging, as well as other imaging markers of cSVD, including lacune, white matter lesions, and cerebral microbleeds, were rated using validated scales. Chronic kidney disease was defined as either reduced estimated glomerular filtration rate or the presence of proteinuria. Results— After adjustments for potential confounders by logistic regression, proteinuria and impaired estimated glomerular filtration rate were correlated with the severity of EPVS in both centrum semiovale (odds ratio [OR] 2.59; 95% confidence interval [CI] 1.19–5.64 and OR 2.37; 95% CI 1.19–4.73) and basal ganglia (OR 5.12; 95% CI 2.70–12.10 and OR 4.17; 95% CI 2.08–8.37). A similar association was also found between proteinuria and low estimated glomerular filtration rate levels and the comprehensive cSVD burden (OR 2.13; 95% CI 1.10–4.14 and OR 5.59; 95% CI 2.58–12.08). Conclusions— Proteinuria and impaired estimated glomerular filtration rate are associated with increasing EPVS severity and, furthermore, accumulated magnetic resonance imaging burden of cSVD in patients with first-ever acute lacunar stroke.

The NINDS-Canadian stroke network vascular cognitive impairment neuropsychology protocols in Chinese

Background and purpose Vascular cognitive impairment (VCI) affects up to half of stroke survivors and predicts poor outcomes. Valid and reliable assessement for VCI is lacking, especially for the Chinese population. In 2005, the National Institute of Neurological Disorders and Stroke and Canadian Stroke Network (NINDS-CSN) Harmonisation workshop proposed a set of three neuropsychology protocols for VCI evaluation. This paper is to introduce the protocol design and to report the psychometric properties of the Chinese NINDS-CSN VCI protocols. Methods Fifty patients with mild stroke (mean National Institute of Health Stroke Scale 2.2 (SD=3.2)) and 50 controls were recruited. The NINDS-CSN VCI protocols were adapted into Chinese. We assessed protocols’ (1) external validity, defined by how well the protocol summary scores differentiated patients from controls using receiver operating characteristics (ROC) curve analysis; (2) concurrent validity, by correlations with functional measures including Stroke Impact Scale memory score and Chinese Disability Assessment for Dementia; (3) internal consistency; and (4) ease of administration. Results All three protocols differentiated patients from controls (area under ROC for the three protocols between 0.77 to 0.79, p<0.001), and significantly correlated with the functional measures (Pearson r ranged from 0.37 to 0.51). A cut-off of 19/20 on MMSE identified only one-tenth of patients classified as impaired on the 5-min protocol. Cronbachs α across the four cognitive domains of the 60-min protocol was 0.78 for all subjects and 0.76 for stroke patients. Conclusions The Chinese NINDS-CSN VCI protocols are valid and reliable for cognitive assessment in Chinese patients with mild stroke.