Xiao-Ling Zhong

Blood Clusterin Levels, rs9331888 Polymorphism, and the Risk of Alzheimer's Disease

Variants in the clusterin gene have been associated with Alzheimers disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. In this study the association of the AD clusterin common risk polymorphism rs9331888 with blood clusterin levels was tested in 104 AD subjects and 104 healthy controls. Blood clusterin levels were significantly elevated in AD patients (p < 0.05). The rs9331888 AD-risk variant was associated with low clusterin mRNA and protein levels in an allele-dose dependent manner in both groups (p < 0.001). This study indicates that the rs9331888 AD-risk variant is associated with low blood clusterin levels.

Anticonvulsant effect of unilateral anterior thalamic high frequency electrical stimulation on amygdala-kindled seizures in rat

Deep brain stimulation (DBS) is an emerging treatment of epilepsy. Anterior nucleus of the thalamus (ANT) is considered to be an attractive target due to its close connection to the limbic structures and wide regions of neocortex. In this study, we examined the effect of unilateral high frequency stimulation (HFS) of the ANT on amygdala-kindled seizures in Wistar rats. When fully-kindled seizures were achieved by daily amygdala kindling, HFS (15 min train of 100 μs pulses at 200 Hz and 450-800 μA) was delivered to the ipsilateral or contralateral ANT immediately before the kindling stimulation for 15 days. HFS of the ipsilateral ANT significantly decreased the incidence of generalized seizures and the mean behavioral seizure stage and afterdischarge duration (ADD), and shortened cumulative ADD and cumulative generalized seizure duration. Furthermore, HFS of the ipsilateral ANT significantly increased the afterdischarge threshold (ADT). Our data suggest that unilateral HFS of the ANT may be an effective method of inhibiting kindled seizures by suppressing the susceptibility to seizures and generating long lasting anti-epileptic effect preventing the recurrence of kindled seizures, providing an alternative to bilateral ANT DBS for refractory epilepsy.

Low-frequency stimulation of bilateral anterior nucleus of thalamus inhibits amygdale-kindled seizures in rats ☆

Brain stimulation with low-frequency is emerging as an alternative treatment for refractory epilepsy. The anterior nucleus thalamus (ANT) is thought to be a key structure in the circuits of seizure generation and propagation. The present study aimed to investigate the effects of low frequency stimulation (LFS) targeting ANT on amygdala-kindled seizures in Sprague-Dawley rats. Electrodes were implanted into the right basolateral amygdala and the right or bilateral ANT of Sprague-Dawley rats. When fully kindled seizures were achieved by daily electrical stimulation of the amygdala, LFS (15 min train of 0.1 ms pulses at 1 Hz and 200-500 μA) was applied to the unilateral or bilateral ANT immediately before the kindling stimulation (pre-treatment). Our study showed that LFS of the bilateral ANT significantly decreased the incidence of generalized seizures (GS) and seizure stage, as well as shortened duration of afterdischarge and GS demonstrating an inhibition of the severity of seizures. Moreover, LFS elevated the afterdischarge threshold (ADT) and GS threshold indicating an inhibition of susceptibility to seizures. On the other hand, LFS of the unilateral ANT failed to show any significance in inhibiting seizures. Our study demonstrated that bilateral LFS in ANT could significantly inhibit amygdala-kindled seizures by preventing both afterdischarge generation and propagation. It provided further evidence for clinical use of LFS in ANT.

Common variant in GAB2 is associated with late-onset Alzheimer's disease in Han Chinese

BACKGROUND GRB-associated binding protein 2 (GAB2) may function as a risk factor in the pathogenesis of Alzheimer disease (AD). A recent large genome-wide association study (GWAS) has identified a significant association of rs10793294 polymorphism within the GAB2 gene with AD in Caucasians. While there are no studies on the association of rs10793294 polymorphism with AD risk in the Chinese population. METHODS The study investigated 358 sporadic late-onset AD (LOAD) and 366 healthy controls matched for sex and age in a Han Chinese population. The rs10793294 polymorphism within the GAB2 gene was genotyped using MALDI-TOF mass spectrometry. RESULTS The C allele of the rs10793294 polymorphism within GAB2 was significantly associated with an increased risk of LOAD (OR=1.33, 95% CI=1.04-1.72, P=0.029). Significance was observed in APOEε4 carriers (genotype P=0.039, allele P=0.016). While in APOE ε4 non-carriers, significant differences were observed in alleles (P=0.039) but not in genotypes (P=0.304). Logistic regression revealed that rs10793294 polymorphism was still strongly associated with LOAD in dominant model (OR=2.58, 95% CI=1.22-5.45, P=0.013) and additive model (OR=1.38, 95% CI=1.05-1.80, P=0.020) after adjusting for age, gender, and the APOE ε4 status. CONCLUSIONS Our findings implicate GAB2 as a susceptibility gene for LOAD in Han Chinese.

NEDD9 is genetically associated with Alzheimer's disease in a Han Chinese population.

Neural precursor cell-expressed, developmentally downregulated 9 (NEDD9) has been suspected to be associated with Alzheimers disease (AD) through participating in the formation of neurite-like membrane extensions and neurite outgrowth to affect the number of neuronal cells/synapses in the brain under stressful conditions. A recent large-scale, multi-tiered association study has identified significant association of a common single nucleotide polymorphism (SNP) rs760678 in the NEDD9 gene with predisposition to late-onset Alzheimers disease (LOAD) in Caucasians. In order to evaluate the involvement of the NEDD9 polymorphism in the risk of sporadic LOAD, we performed an independent case-control association study to analyze the genotype and allele distributions of the NEDD9 rs760678 polymorphism in a Han Chinese population (383 LOAD cases and 369 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P=0.003, allele P=0.002). After stratification by APOE ε4-carrying status, the C allele of rs760678 was only significantly associated with LOAD in non-APOE ε4 allele carriers (OR=1.43, 95%, CI=1.06-1.94, P=0.024). In addition, a logistic regression analysis also conferred positive association between the SNP rs760678 and LOAD (dominant model: OR=2.10, 95% CI=1.23-3.58, P=0.007; additive model: OR=1.37, 95% CI=1.09-1.74, P=0.008) after adjustment for age, gender, and the APOE ε4 carrier status. The study demonstrated a significant association between the tested SNP and LOAD, indicating that NEDD9 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.

Lack of association between rs597668 polymorphism near EXOC3L2 and late-onset Alzheimer's disease in Han Chinese.

Recently, an international genome-wide association study (GWAS) additionally found rs597668 near EXOC3L2/BLOC1S3/MARK4 was a new genome-wide significance locus associated with late-onset Alzheimers disease (LOAD) in Caucasians. Follow-up replication studies were conducted almost exclusively in Caucasians, and the effects of the risk locus in other populations are as yet unknown. This study investigated the GWAS-associated locus near EXOC3L2 in 1205 unrelated Northern Han Chinese subjects comprising 598 LOAD patients and 607 healthy controls matched for gender and age. The results showed no significant differences in the genotypic or allelic distributions of rs597668 polymorphism between LOAD cases and healthy controls (genotype: P=0.653; allele: P=0.603), even after stratification for apolipoprotein E (APOE) ɛ4 status and statistical adjustment for age, gender and APOE ɛ4 status. This study suggests that the rs597668 polymorphism near EXOC3L2 may not play a major role in the susceptibility to LOAD in the Northern Han Chinese population.