Guoqiang Fei

Decreased serum ceruloplasmin levels characteristically aggravate nigral iron deposition in Parkinson’s disease

In vivo and post-mortem studies have demonstrated that increased nigral iron content in patients with Parkinsons disease is a prominent pathophysiological feature. However, the mechanism and risk factors associated with nigral iron deposition in patients with Parkinsons disease have not been identified and represent a key challenge in understanding its pathogenesis and for its diagnosis. In this study, we assessed iron levels in patients with Parkinsons disease and in age- and gender-matched control subjects by measuring phase values using magnetic resonance based susceptibility-weighted phase imaging in a 3T magnetic resonance system. Phase values were measured from brain regions including bilateral substantia nigra, globus pallidus, putamen, caudate, thalamus, red nucleus and frontal white matter of 45 patients with Parkinsons disease with decreased or normal serum ceruloplasmin levels, together with age- and gender-matched control subjects. Correlative analyses between phase values, serum ceruloplasmin levels and disease severity showed that the nigral bilateral average phase values in patients with Parkinsons disease were significantly lower than in control subjects and correlated with disease severity according to the Hoehn and Yahr Scale. The Unified Parkinsons Disease Rating Scale motor scores from the clinically most affected side were significantly correlated with the phase values of the contralateral substantia nigra. Furthermore, nigral bilateral average phase values correlated highly with the level of serum ceruloplasmin. Specifically, in the subset of patients with Parkinsons disease exhibiting reduced levels of serum ceruloplasmin, we found lowered nigral bilateral average phase values, suggesting increased nigral iron content, while those patients with normal levels of serum ceruloplasmin exhibited no changes as compared with control subjects. These findings suggest that decreased levels of serum ceruloplasmin may specifically exacerbate nigral iron deposition in patients with Parkinsons disease. Combining susceptibility-weighted phase imaging with serum ceruloplasmin determination is likely to be useful for the diagnosis and assessment of a subset of patients with Parkinsons disease.

Powerful beneficial effects of benfotiamine on cognitive impairment and β-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice

Reduction of glucose metabolism in brain is one of the main features of Alzheimers disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimers disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimers disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3alpha and -3beta, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimers disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimers disease treatment.

Nigral iron deposition occurs across motor phenotypes of Parkinson’s disease

Background and purpose:  To investigate whether brain iron deposition correlates with motor phenotypic expressions of Parkinson’s disease.

Measurement of Blood Thiamine Metabolites for Alzheimer's Disease Diagnosis

Background Brain glucose hypometabolism is an invariant feature and has significant diagnostic value for Alzheimers disease. Thiamine diphosphate (TDP) is a critical coenzyme for glucose metabolism and significantly reduced in brain and blood samples of patients with Alzheimers disease (AD). Aims To explore the diagnostic value of the measurement of blood thiamine metabolites for AD. Methods Blood TDP, thiamine monophosphate, and thiamine levels were detected using high performance liquid chromatography (HPLC). The study included the exploration and validation phases. In the exploration phase, the samples of 338 control subjects and 43 AD patients were utilized to establish the models for AD diagnosis assayed by receiver operating characteristic (ROC) curve, including the variable γ that represents the best combination of thiamine metabolites and age to predict the possibility of AD. In the validation phase, the values of models were further tested for AD diagnosis using samples of 861 control subjects, 81 AD patients, 70 vascular dementia patients, and 13 frontotemporal dementia patients. Results TDP and the γ exhibited significant and consistent values for AD diagnosis in both exploration and validation phases. TDP had 0.843 and 0.837 of the areas under ROC curve (AUCs), 77.4% and 81.5% of sensitivities, and 78.1% and 77.2% of specificities respectively in the exploration and validation phases. The γ had 0.938 and 0.910 of AUCs, 81.4% and 80.2% of sensitivities, and 90.5% and 87.2% of specificities respectively in the exploration and validation phases. TDP and the γ can effectively distinguish AD from vascular dementia (64.3% for TDP, 67.1% for γ) and frontotemporal dementia (84.6% for TDP, 100.0% for γ). Interpretation. The measurement of blood thiamine metabolites by HPLC is an ideal diagnostic test for AD with inexpensive, easy to perform, noninvasive merits.

Serum microRNA-133b is associated with low ceruloplasmin levels in Parkinson's disease

INTRODUCTION The cause of low serum ceruloplasmin levels in Parkinsons disease (PD) remains to be clarified. In this study, we explored serum miR-133b expression to determine whether it correlates with serum ceruloplasmin level in PD patients. METHODS Forty-six patients with PD and forty-six control subjects were evaluated for miR-133b expression using qRT-PCR. The serum ceruloplasmin levels in all of the subjects were also determined. RESULTS Serum miR-133b expression levels were significantly decreased in PD patients compared with those in the control subjects. Furthermore, PD patients with low serum ceruloplasmin levels also exhibited significantly lower expression of miR-133b compared with that of patients with normal ceruloplasmin levels. MiR-133b expression was correlated with the ceruloplasmin level in patients with PD, whereas no correlation was found between miR-133b and disease severity or motor phenotype. CONCLUSION Our observations suggest that miR-133b might be involved in ceruloplasmin dysmetabolism in PD patients and a further investigation is warranted to confirm this hypothesis.

Benfotiamine prevents increased β-amyloid production in HEK cells induced by high glucose

ObjectiveTo determine whether high glucose enhances β-amyloid (Aβ) production in HEK293 Swedish mutant (APPsw) cells with Aβ precursor protein (APP) overexpression, and whether under this condition benfotiamine reduces the increased Aβ production.MethodsHEK293 APPsw cells were cultured with different concentrations of glucose for different times. The Aβ content in the supernatant was determined by ELISA. To investigate the mechanism by which benfotiamine reduced Aβ production, glycogen synthase kinase-3 (GSK-3) activity and expression were measured after the cells were cultured with 5.5 g/L glucose for 12 h.ResultsWith 1.0, 3.0, 4.5, 5.5, 6.5, 7.5, 8.5, or 10.5 g/L glucose, Aβ production by HEK293 APPsw cells was highest in the presence of 5.5 g/L glucose for 6 and 12 h. The difference in Aβ content between 5.5 and 1.0 g/L was most marked after incubation for 12 h. Benfotiamine at 20 and 40 μg/mL significantly reduced Aβ production in cells incubated with 5.5 g/L glucose for 12 h. Moreover, 40 μg/mL benfotiamine significantly enhanced the ratio of phosphorylated GSK-3 to total GSK-3, together with consistent down-regulation of GSK-3 activity.ConclusionHigh glucose increases Aβ production by HEK293 APPsw cells while benfotiamine prevents this increase. This is correlated with the modulation of GSK-3 activity.

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

Growing evidence has indicated that iron deposition in the substantia nigra plays an important role in Parkinson’s disease (PD). However, the underlying mechanism is still elusive. Using primary dopaminergic neurons and SH-SY5Y cells cultured in vitro, we observed that iron loading increased α-synuclein and reactive oxygen species (ROS) levels in these cells but did not affect the intracellular α-synuclein mRNA levels. Furthermore, iron loading significantly downregulated Beclin-1 levels and decreased the ratio of microtubule-associated protein 1 light chain 3 isoforms (LC3 II/LC3 I). However, a significant change in the levels of autophagy-related gene 5 (Atg5) was not observed in either neurons or SH-SY5Y cells after iron treatment. After treatment with rapamycin, the iron loading-induced increase in the α-synuclein level was significantly reversed and ROS generation was alleviated in both cultured neurons and SH-SY5Y cells. These results indicate that the inhibition of autophagy is critical for the pathological alterations in α-synuclein induced by iron loading. Moreover, treatment with vitamin E did not affect the increase in the α-synuclein levels but significantly eliminated the iron-induced ROS production. Together, our study shows that autophagy dysfunction contributes to iron-induced α-synuclein pathology.

Correlat ion of thiamine metabolite levels with cognitive function in the non-demented elderly

Thiamine metabolism is critical for glucose metabolism and also vital for brain function, which is susceptible to decline in the elderly. This study aimed to investigate whether thiamine metabolites correlate with cognitive function in the non-demented elderly and their impact factors. Volunteers >60 years old were recruited and their blood thiamine metabolites and Mini-Mental State Examination (MMSE) scores were measured. The apolipoprotein E (APOE) genotype, routine blood parameters, liver and kidney function, and levels of fasting blood glucose and triglycerides were also measured. The results showed that the thiamine diphosphate (TDP) level weakly correlated with MMSE score in the non-demented elderly. Participants with high TDP levels performed better in Recall and Attention and Calculation than those with low TDP. TDP levels were associated with the APOE ε2 allele, body mass index, hemoglobin level, fasting blood glucose, and triglycerides. Our results suggest that TDP, which is easily affected by many factors, impacts cognitive function in the elderly.

High thiamine diphosphate level as a protective factor for Alzheimer’s disease

Abstract Objectives Thiamine diphosphate (TDP) is an indispensable coenzyme for three key enzymes in glucose metabolism. Reduced TDP levels in patients with Alzheimer’s disease (AD) has been widely demonstrated and is a diagnostic biomarker for the disease. In this study, we further explored the correlation between altered TDP metabolism and AD along with other risk factors. Methods A 1:1 case-control study was employed with 90 AD patients and 90 control subjects with normal-range cognitive abilities as assayed by the Mini Mental Status Evaluation. Age (≤2 years variation), gender, and educational background were strictly matched. Levels of the main thiamine metabolites in whole blood samples, including TDP, thiamine monophosphate, and thiamine, were assayed using high-performance liquid chromatography. Apolipoprotein E genotypes, haemoglobin, and several metabolic factors (fasting glucose, uric acid, triglyceride, and total cholesterol) associated with AD were also measured. Results The odds ratio of TDP level for AD was 0.95 (with TDP level as a continuous variable) or 0.09 (with TDP level as a dichotomized variable with a cut-off value of 99.48 nmol/L). Blood TDP levels were significantly decreased in female AD patients compared to male AD patients. No correlations were identified between TDP levels and several metabolic factors (fasting glucose, uric acid, triglyceride, and total cholesterol). Conclusions TDP is a protective factor for AD and its protective efficacy may be independent of other metabolic factors. The difference of TDP levels between genders may be another possible explanation for the higher prevalence of AD in females.

Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer’s disease, whereas amyloid deposition does not

BackgroundThe underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer’s disease (AD), remains elusive.MethodsPositron emission tomography with 2-[18F]fluoro-2-deoxy-d-glucose (FDG-PET) was used to evaluate brain glucose metabolism, presented as the rate of 2-[18F]fluoro-2-deoxy-d-glucose standardized uptake value ratio (FDG SUVR) in patients with AD or control subjects and in mice with or without thiamine deficiency induced by a thiamine-deprived diet. Brain amyloid-β (Aβ) deposition in patients with clinically diagnosed AD was quantified by performing assays using 11C-Pittsburgh compound B PET. The levels of thiamine metabolites in blood samples of patients with AD and control subjects, as well as in blood and brain samples of mice, were detected by high-performance liquid chromatography with fluorescence detection.ResultsFDG SUVRs in frontal, temporal, and parietal cortices of patients with AD were closely correlated with the levels of blood thiamine diphosphate (TDP) and cognitive abilities, but not with brain Aβ deposition. Mice on a thiamine-deprived diet manifested a significant decline of FDG SUVRs in multiple brain regions as compared with those in control mice, with magnitudes highly correlating with both brain and blood TDP levels. There were no significant differences in the changes of FDG SUVRs in observed brain regions between amyloid precursor protein/presenilin-1 and wild-type mice following thiamine deficiency.ConclusionsWe demonstrate, for the first time to our knowledge, in vivo that TDP reduction strongly correlates with brain glucose hypometabolism, whereas amyloid deposition does not. Our study provides new insight into the pathogenesis and therapeutic strategy for AD.