Chunjiu Zhong

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.

Oxidative stress in Alzheimer's disease

Oxidative stress plays a significant role in the pathogenesis of Alzheimer’s disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, inflammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.

Impaired hippocampal neurogenesis is involved in cognitive dysfunction induced by thiamine deficiency at early pre-pathological lesion stage

It has not been reported whether thiamine deficiency (TD) affects hippocampal neurogenesis or not. Here, we explored the influence of TD at early pre-pathological lesion stage on hippocampal neurogenesis and the correlation between affected hippocampal neurogenesis and cognitive dysfunction. We prepared TD mouse model by feeding a thiamine-depleted diet. Learning and memory functions of TD mice were tested with Y-maze. Hippocampal neurogenesis was studied with BrdU, PCNA, Dcx, and NeuN immunohistochemical staining. The results showed significant decline in learning ability and hippocampal neurogenesis simultaneously since 9-days of treatment when the model mice did not exhibit regular pathological lesion, the loss of cholinergic neurons, decrease of NeuN-positive hippocampal cell, and abnormal long-term potentiation of hippocampal CA1 and CA3. Re-administering thiamine reversed the weakened learning ability as well as the impaired hippocampal neurogenesis induced by TD at early pre-pathological lesion stage. The present study demonstrated that hippocampal neurogenesis was vulnerable to TD and the impaired hippocampal neurogenesis is greatly involved in cognitive dysfunction induced by TD at early pre-pathological lesion stage.

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.

Exposure to Pyrithiamine Increases β-Amyloid Accumulation, Tau Hyperphosphorylation, and Glycogen Synthase Kinase-3 Activity in the Brain

Decreased thiamine-dependent enzyme activity and/or thiamine deficiency (TD) have been linked to Alzheimer’s disease (AD). In this study, we administered pyrithiamine, an anti-thiamine compound, to both APP/PS1 transgenic mice and wild-type littermate control mice; alternatively, we induced TD by thiamine-depleted diet. Pyrithiamine treatment and diet-induced TD impaired the memory of wild-type mice, but had little effect on APP/PS1 mice. Pathophysiologically, pyrithiamine treatment and diet-induced TD aggravated β-amyloid accumulation in the brain. This was demonstrated by increased β-amyloid in the brains of wild-type mice using ELISA and by the number of amyloid plaques in the brains of APP/PS1 transgenic mice using immunochemical staining. Also, enhanced numbers of phosphorylated Tau-positive cells were observed in both APP/PS1 transgenic and wild-type mice. Furthermore, pyrithiamine decreased the phosphorylation rates of glycogen synthase kinase (GSK)-3β and raised its enzymatic activity, but had little influence on GSK-3α. Diet-induced TD reduced the phosphorylated rates and increased the activities of GSK-3, GSK-3α, and GSK-3β. These results suggest that when sufficient thiamine supplement is administered, pyrithiamine can cause AD-like pathological alterations similar to that of diet-induced TD.

Decreased transketolase activity contributes to impaired hippocampal neurogenesis induced by thiamine deficiency.

Thiamine deficiency (TD) impairs hippocampal neurogenesis. However, the mechanisms involved are not identified. In this work, TD mouse model was generated using a thiamine‐depleted diet at two time points, TD9 and TD14 for 9 and 14 days of TD respectively. The activities of pyruvate dehydrogenase (PDH), α‐ketoglutamate dehydrogenase (KGDH), glucose‐6‐phosphate dehydrogenase (G6PD), and transketolase (TK), as well as on the contents of NADP+ and NADPH were determined in whole mouse brain, isolated cortex, and hippocampus of TD mice model. The effects of TK silencing on the growth and migratory ability of cultured hippocampal progenitor cells (HPC), as well as on neuritogenesis of hippocampal neurons were explored. The results showed that TD specifically reduced TK activity in both cortex and hippocampus, without significantly affecting the activities of PDH, KGDH, and G6PD in TD9 and TD14 groups. The level of whole brain and hippocampal NADPH in TD14 group were significantly lower than that of control group. TK silencing significantly inhibited the proliferation, growth, and migratory abilities of cultured HPC, without affecting neuritogenesis of cultured hippocampal neurons. Taken together, these results demonstrate that decreased TK activity leads to pentose‐phosphate pathway dysfunction and contributes to impaired hippocampal neurogenesis induced by TD. TK and pentose‐phosphate pathway may be considered new targets to investigate hippocampal neurogenesis.

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.

Environmental factors in the development and progression of late-onset Alzheimer＇s disease

Late-onset Alzheimer’s disease (LOAD) is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.