Subcortical nuclei in Alzheimer's disease: a volumetric and diffusion kurtosis imaging study.

Background Previous studies revealed that subcortical nuclei were harmed in the process of Alzheimer's disease (AD). Purpose To investigate the volumetric and diffusion kurtosis imaging (DKI) parameter changes of subcortical nuclei in AD and their relationship with cognitive function. Materials and Methods A total of 17 mild AD patients, 15 moderate to severe AD patients, and 16 controls underwent neuropsychological tests and magnetic resonance imaging (MRI) scans. Volume, mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA) were measured in hippocampus, thalamus, caudate, putamen, pallidum, and amygdala. MRI parameters were compared. Correlation analysis was performed between subcortical nuclei volume, DKI parameters, and MMSE score. Results Significant volume reduction was seen in the left hippocampus in mild AD, and the bilateral hippocampus, thalamus, putamen, left caudate, and right amygdala in moderate to severe AD ( P < 0.05). Increased MD values were observed in the left hippocampus, left amygdala, and right caudate in mild AD, and the bilateral hippocampus and right amygdala in moderate to severe AD ( P < 0.05). Decreased MK values were observed only in the bilateral hippocampus in moderate to severe AD ( P < 0.05). No group significances were found in FA value. MMSE score was positively correlated with the volume of the bilateral hippocampus, thalamus, and putamen, and MK value of the left hippocampus ( P < 0.05). A negative correlation was found with the MD value of the bilateral hippocampus and left amygdala ( P < 0.05). Conclusion Mild AD mainly has microscopic subcortical changes revealed by increased MD value, and moderate to severe AD mainly has macroscopic subcortical changes revealed by volume reduction. MK is more sensitive in severe AD than mild AD.

Edaravone Attenuates the Proinflammatory Response in Amyloid-ß-Treated Microglia by Inhibiting NLRP3 Inflammasome-Mediated IL-1ß Secretion.

BACKGROUND/AIMS: Microglial activation is an important pathological feature in the brains of patients with Alzheimer's disease (AD), and amyloid-ß (Aß) peptides play a crucial role in microglial activation. In addition, edaravone (EDA) was recently shown to suppress oxidative stress and proinflammatory cytokine production in APPswePS1dE9 (APP/PS1) mice. However, the mechanism by which EDA inhibits the Aß-induced proinflammatory response in microglia is poorly understood. METHODS: The mitochondrial membrane potential (∆ψm) was evaluated using JC-1 staining. Intracellular reactive oxygen species (ROS) and mitochondrial ROS levels were detected using CM-H2DCFDA and MitoSOXTM Red, respectively. The levels of CD11b, NLRP3, pro-caspase-1 and manganese superoxide dismutase (SOD-2) were observed by western blotting, and the levels of interleukin-1beta (IL-1ß) in culture supernatants were quantified using an ELISA kit. RESULTS: Aß induced microglia activation and mitochondrial dysfunction. In addition, mitochondrial dysfunction was associated with ROS accumulation and activation of the NLRP3 inflammasome. Importantly, Aß induced activation of the NLRP3 inflammasome, leading to caspase-1 activation and IL-1ß release in microglia. Moreover, EDA obviously attenuated the depolarization of ∆ψm, reduced mitochondria-derived ROS production and increased SOD-2 activity, resulting in the suppression of NLRP3 inflammasome-mediated IL-1ß secretion in Aß-treated microglia. CONCLUSION: EDA is a mitochondria-targeted antioxidant and exhibits anti-inflammatory effects on Aß-treated microglia.

Relationships between CETP genetic polymorphisms and Alzheimer's disease risk: a meta-analysis.

This meta-analysis was performed to evaluate the relationships between single-nucleotide polymorphisms in the CETP gene and the risk of Alzheimer's disease (AD). The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched from inception through October 1, 2013, without language restrictions. Nine case-control studies with a total of 2172 AD patients and 8017 healthy controls were involved in this meta-analysis. Two common polymorphisms (rs708272 T>C and rs5882 A>G) in the CETP gene were assessed. Our meta-analysis results showed that CETP rs5882 A>G polymorphism might increase the risk of AD (A allele vs. G allele: odds ratio [OR]=1.11, 95% confidence interval [95% CI]=1.02-1.21, p=0.014; AA+AG vs. GG: OR=1.28, 95% CI=1.07-1.52, p=0.006; AA vs. GG: OR=1.32, 95% CI=1.10-1.70, p=0.003; AA vs. AG: OR=1.25, 95% CI=1.03-1.50, p=0.020; respectively). However, we found no correlations of CETP rs708272 T>C polymorphism with AD risk (all p>0.05). Subgroup analysis by ethnicity suggested positive associations between CETP rs5882 A>G polymorphism and an increased risk of AD among Caucasians (A allele vs. G allele: OR=1.10, 95% CI=1.01-1.21, p=0.014; AA+AG vs. GG: OR=1.34, 95% CI=1.06-1.69, p=0.015; AA vs. GG: OR=1.35, 95% CI=1.07-1.70, p=0.011; respectively), but not among Asians (all p>0.05). No associations were found between CETP rs708272 T>C polymorphism and AD risk among both Asians and Caucasians (all p>0.05). Our findings provide empirical evidence that CETP rs5882 A>G polymorphism may contribute to susceptibility to AD, especially among Caucasians. However, CETP rs708272 T>C polymorphism does not seem to be an important determinant in the pathogenesis of AD.

Glycogen synthase kinase-3 regulates production of amyloid-ß peptides and tau phosphorylation in diabetic rat brain.

The pathogenesis of diabetic neurological complications is not fully understood. Diabetes mellitus (DM) and Alzheimer's disease (AD) are characterized by amyloid deposits. Glycogen synthase kinase-3 (GSK-3) plays an important role in the pathogenesis of AD and DM. Here we tried to investigate the production of amyloid-ß peptides (A ß) and phosphorylation of microtubule-associated protein tau in DM rats and elucidate the role of GSK-3 and Akt (protein kinase B, PKB) in these processes. Streptozotocin injection-induced DM rats displayed an increased GSK-3 activity, decreased activity and expression of Akt. And A ß 40 and A ß 42 were found overproduced and the microtubule-associated protein tau was hyperphosphorylated in the hippocampus. Furthermore, selective inhibition of GSK-3 by lithium could attenuate the conditions of A ß overproduction and tau hyperphosphorylation. Taken together, our studies suggest that GSK-3 regulates both the production of A ß and the phosphorylation of tau in rat brain and may therefore contribute to DM caused AD-like neurological defects.

Use of diffusion tensor imaging for evaluating changes in the microstructural integrity of white matter over 3 years in patients with amnesic-type mild cognitive impairment converting to Alzheimer's disease.

BACKGROUND AND PURPOSE: Patients with amnestic mild cognitive impairment (aMCI) are at risk of developing Alzheimer's disease (AD). It is therefore important to identify biomarkers of conversion to AD. This study examined whether the integrity of white matter can predict this conversion. METHODS: Magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and neuropsychological features of aMCI subjects (n = 41) were compared with normal controls (n = 20) for 12-36 months. RESULTS: Compared to controls, 22 aMCI subjects had lower fractional anisotropy (FA) values in the cingulate fasciculus (CF) at baseline, and 19 of those converted to AD during follow-up. Only two of the other 19 aMCI patients converted to AD. Compared to baseline, AD converters showed lower FA values in the anterior frontal lobe, temporal lobe, hippocampus, inferior fronto-occipital fascicles, corpus callosum genu and CF, and higher apparent diffusion coefficient values in the temporal lobe and hippocampus. CONCLUSIONS: Those aMCI subjects with lower than normal FA values in the CF were more likely to convert to AD. The connectivity of the hippocampus and cingulate bundles may be affected in the early stage of AD. Impairment of white matter and fiber bundles was more severe at the AD stage than the aMCI stage.

A melatonin-based fluorescence method for the measurement of mitochondrial complex III function in intact cells.

Mitochondrial complex III (MC-3) plays a pivotal role in electron transfer and oxidative phosphorylation. Impaired MC-3 functions may contribute to a variety of diseases by interrupting normal bioenergetics and increasing reactive oxygen production and oxidative stress. Currently, MC-3 function is assessed by measuring the cytochrome c reductase activity spectrophotometrically in isolated mitochondria or MC-3. The cytoplasmic microenvironment critical for mitochondrial complex functions may be depleted during these isolation processes. The development of a reliable method to measure MC-3 activities in intact cells or tissues is highly desirable. This report describes a novel fluorescence-based method to assess MC-3 functions, i.e., Qi site electron transfer, in the intact cells. Human mesangial and teratocarcinoma NT2 cells were used to demonstrate that melatonin-induced oxidation of 2',7'-dichlorodihydrofluorescein (H2 DCF) was inhibited by antimycin A, the MC-3 Qi site-specific inhibitor, but not by myxothiazol, the MC-3 Qo site-specific inhibitor, nor rotenone, the mitochondrial complex I inhibitor. These results indicate that melatonin-induced oxidation of H2 DCF is reflecting MC-3 Qi site electron transfer activities. Modifying structures of the side groups at the R3 and R5 positions of the indole ring of melatonin diminished its efficacy for inducing H2 DCF oxidation, suggesting a specific interaction of melatonin with the MC-3 Qi site. These results suggest that the fluorogenic property of melatonin-induced H2 DCF oxidation provides a MC-3 Qi site electron transfer-specific measurement in intact cells. Interestingly, using this method, the Qi site electron transfer activity in transformed or immortalized cells was found to be significantly higher than the nontransformed cells.

The neuroprotective effect of losartan through inhibiting AT1/ASK1/MKK4/JNK3 pathway following cerebral I/R in rat hippocampal CA1 region.

AIMS: It has been well documented that angiotensin II type 1 (AT(1) ) receptor blockers (ARBs) are known to attenuate neural damage and the c-Jun N-terminal protein kinase 3 (JNK3) pathway and caspase-3 signal are involved in neuronal cell death following cerebral ischemia/reperfusion (I/R). In this study, we first showed that losartan could protect neurons against cerebral I/R-induced injury. METHODS: Cerebral ischemia model was induced by four-vessel occlusion. Antisense oligodeoxynucleotides (ODNs) against AT1 receptor and losartan were used to detect whether the AT1 receptor implicated in cerebral I/R. Immunoprecipitation (IP) and immunoblotting (IB) were used to detect the interactions between ß-arrestin-2 and AT1/apoptosis signal-regulating kinase 1 (ASK1)/MAP kinase kinase 4 (MKK4) signaling module following cerebral I/R. RESULTS: First, losartan decreased cerebral I/R-induced neuronal death. Second, losartan depressed the ß-arrestin-2-assembled AT1/ASK1/MKK4 signaling module. Third, losartan depressed the activation of c-jun, JNK3, Bcl-2, caspase-3 and the release of cytochrome c from mitochondria to cytoplasm. CONCLUSION: Taken together, losartan could attenuate neural damage following the cerebral I/R via inhibiting the ß-arrestin-2-assembled AT1/ASK1/MKK4 signaling module and depressing the activation of c-jun, JNK3, and caspase-3 and the release of cytochrome c.

Clinicopathological features of Churg-Strauss syndrome with severe nerve degeneration: a case report.

Churg-Strauss syndrome (CSS) is a rare autoimmune vasculitis of unknown etiology that involves small- and medium-sized blood vessels. Its onset is thought to be associated with adult-onset asthma, and vasculitis typically involves vessels in the lungs. However, due to increased blood and tissue eosinophilia, vasculitis may result in the involvement multiple systems of (neurological, skin, etc.). We report a case of CSS with manifestations that included skin purpura and severe peripheral nerve degeneration in a 56-year-old woman with a recent history of asthma. After the treatment with methylprednisolone and standard immunosuppressive therapy, her rashes resolved, there were no acute asthma attacks, and the numbness in her lower limbs improved.

The value of diffusion tensor imaging in the differential diagnosis of subcortical ischemic vascular dementia and Alzheimer's disease in patients with only mild white matter alterations on T2-weighted images.

BACKGROUND: Diffusion tensor imaging (DTI) is a form of functional magnetic resonance imaging (MRI) that allows examination of the microstructural integrity of white matter in the brain. Dementia is a neurodegenerative disease, and DTI can provide indirect insights of the microstructural characteristics of brains in individuals with different forms of dementia. PURPOSE: To evaluate the value of DTI in the diagnosis and differential diagnosis of patients with subcortical ischemic vascular dementia (SIVD) and Alzheimer's disease (AD). MATERIAL AND METHODS: The study included 40 patients (20 AD patients and 20 SIVD patients) and 20 normal controls (NC). After routine MRI and DTI, fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were measured and compared in regions of interest (ROI). RESULTS: Compared to NC and AD patients, SIVD patients had lower FA values and higher ADC values in the inferior-fronto-occipital fascicles (IFOF), genu of the corpus callosum (GCC), splenium of the corpus callosum (SCC), and superior longitudinal fasciculus (SLF). Compared to controls and SIVD patients, AD patients had lower FA values in the anterior frontal lobe, temporal lobe, hippocampus, IFOF, GCC, and CF; and higher ADC values in the temporal lobe and hippocampus. CONCLUSION: DTI can be used to estimate the white matter impairment in dementia patients. There were significant regional reductions of FA values and heightened ADC values in multiple regions in SIVD patients compared to AD patients. When compared with conventional MRI, DTI may provide a more objective method for the differential diagnosis of SIVD and AD disease patients who have only mild white matter alterations on T2-weighted imaging.

Comparison of diffusion tensor image study in association fiber tracts among normal, amnestic mild cognitive impairment, and Alzheimer's patients.

AIM: To compare diffusion tensor image (DTI) study in association fiber tracts among normal control (NC), amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) subjects. To assess diagnostic value of DTI in aMCI and differential diagnosis of DTI study between aMCI and AD. MATERIAL AND METHODS: DTI was used to assess changes in cerebral association fiber tracts in NC, aMCI, and AD subjects (n = 20/group). Regions of interest included the inferior fronto-occipital fascicles (IFOF), superior longitudinal fascicles and cingulum tract, genu of corpus callosum (Gcc) was set right, splenium of corpus callosum was set left. Bilateral fractional anisotropy (FA) and apparent diffusion coefficient values were compared in three groups. RESULTS: Relative to NC, aMCI subjects had significantly different FA values for the IFOF and cingulum tract, while AD subjects had significantly different FA values of IFOF, Gcc, and cingulum tract. Relative to aMCI, AD subjects had significantly different FA values of cingulum tract. CONCLUSION: Based on the results, DTI could be used as a diagnostic method for aMCI with abnormal changes in IFOF and cingulum tract. DTI could also be used for differential diagnosis of aMCI and AD by comparing FA values of the cingulum tract. Abnormal FA values of IFOF, Gcc, and cingulum tract in AD patients may help to elucidate the pathological processes in this disease.

[Efficacy and safety of Deanxit combined with Wuling Capsule in treating post-stroke depression: a randomized controlled trial].

OBJECTIVE: To evaluate the safety and efficacy of Wuling Capsule combined with Deanxit in treating post-stroke depression (PSD). METHODS: One hundred and fourteen patients with PSD were randomly divided into Wuling Capsule-treated group (n=39), Deanxit-treated group (n=37) and Wuling Capsule plus Deanxit-treated group (n=38). Patients in Wuling Capsule-treated group were administered with three Wuling Capsules three times a day, and patients in Deanxit-treated group were administered with Deanxit 10.5 mg twice daily, while patients in the Wuling Capsule plus Deanxit-treated group were administered with both Wuling Capsule and Deanxit. Patients in the three groups were all treated for six weeks. Treatment efficacy was evaluated with Hamilton Depression Scale (HAMD) and the side effects were evaluated with Treatment Emergent Symptom Scale (TESS) before treatment and after 2-, 4-, and 6-week treatment. The blood and urine routine examinations were performed, and the hepatorenal functions and electrocardiogram were examined as well. RESULTS: There was no statistical difference in the total efficacy rate between Wuling Capsule-treated group and Deanxit-treated group (64.1% vs 64.9%, P>0.05), but the total efficacy rate of Wuling Capsule plus Deanxit-treated group was higher than that of the monotherapy (89.5% vs 64.1%, 89.5% vs 64.9%, P<0.05). There were no significant side effects in Wuling Capsule-treated group, while the incidence of side effects was 9% in both groups administered with Deanxit. CONCLUSION: The efficacy of Wuling Capsule plus Deanxit is better than that of the monotherapy in treating PSD.