Search

Thiamine-dependent processes are critical in cerebral glucose metabolism, it is abnormity induces oxidative stress, inflammation and neurodegeneration. Nod-like receptor protein-3 (NLRP3) inflammasome-mediated inflammation is closely related to neurologic diseases and can be activated by oxidative stress. However, the impact of thiamine deficiency on NLRP3 inflammasome activation remains unknown. In this study, we found that NLRP3 inflammasomes were significantly activated in the microglia of thiamine deficiency mice model. In contrast, benfotiamine dampened inflammation NLRP3 mediated in BV2 cells stimulated with LPS and ATP through reducing mitochondrial reactive oxygen species levels and mitigating autophagy flux defect. These data identify an important role of thiamine metabolism in NLRP3 inflammasome activation, and correcting thiamine metabolism through benfotiamine provides a new therapeutic strategy for NLRP3 inflammasome related neurological, metabolic, and inflammatory diseases.

Background: Microglia play diverse roles in Alzheimer’s disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD. Objective: To determine whether microglia intracellular metabolism changes dynamically in different stages of AD. Methods: Microglia were extracted from APPSwe/PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by immunofluorescence staining. Results: Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes were enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period. Conclusion: Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-β deposition.

Lei Sheng,1,* Wei Cao,2,* Pingping Lin,3 Weili Chen,1 Hongrong Xu,1 Chunjiu Zhong,4 Fei Yuan,1 Hanjing Chen,1 Hui Li,1 Chao Liu,1 Mengjie Yang,1 Xuening Li1 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Rixin Biotechnology Co., Ltd, Shanghai, 200237, People’s Republic of China; 3Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, Shandong, 266071, People’s Republic of China; 4Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuening LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, 200032, People’s Republic of ChinaTel +86 21 3158 7860Fax +86 21 6443 7963Email li.xuening@zs-hospital.sh.cnPurpose: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials.Methods: Healthy subjects were sequentially enrolled into one of five SAD (150– 1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4– 9, followed by a single morning dose on day 10.Results: In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC.Conclusion: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.Keywords: Alzheimer’s disease, benfotiamine, thiamine, thiamine diphosphate, pharmacokinetics

The physiological functions of endogenous amyloid-β (Aβ), which plays important role in the pathology of Alzheimer's disease (AD), have not been paid enough attention. Here, we review the multiple physiological effects of Aβ, particularly in regulating synaptic transmission, and the possible mechanisms, in order to decipher the real characters of Aβ under both physiological and pathological conditions. Some worthy studies have shown that the deprivation of endogenous Aβ gives rise to synaptic dysfunction and cognitive deficiency, while the moderate elevation of this peptide enhances long term potentiation and leads to neuronal hyperexcitability. In this review, we provide a new view for understanding the role of Aβ in AD pathophysiology from the perspective of physiological meaning.

Background We aimed to investigate neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features in the locus coeruleus of de novo Parkinson's disease patients with different cognitive states and to determine whether these features are associated with cognitive impairment. Methods Three groups of subjects were recruited in this study, including patients with de novo PD with mild cognitive impairment (n = 23), patients with de novo PD without cognitive impairment (n = 48), and control subjects (n = 32). All subjects underwent clinical evaluations, as well as MRI scanning. The contrast-to-noise ratio of the locus coeruleus in the neuromelanin-sensitive MRI images and cortical thickness were measured. Results The contrast-to-noise ratio of the locus coeruleus in PD patients with mild cognitive impairment was significantly lower than that of controls (P = 0.016). The contrast-to-noise ratio of the locus coeruleus for PD patients without cognitive impairment was intermediate between that of controls and PD patients with mild cognitive impairment. Furthermore, multiple linear regression analysis showed that the contrast-to-noise ratio of the locus coeruleus was negatively associated with performance on the Trail Making Test B in all PD patients, controlling for age, sex, years of education, the Unified Parkinson's Disease Rating Scale motor scores from right upper limb, Geriatric Depression Rating Scales scores, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores, and cortical thickness. Conclusions Dysfunction of the locus coeruleus neurons may partly contribute to the decline in executive function in early de novo PD. In the future, the locus coeruleus-norepinephrine system might be targeted for early-intervention strategies in PD patients. © 2019 International Parkinson and Movement Disorder Society.

Thiamine deficiency contributes to several human diseases including Alzheimer's. As its biologically active form, thiamine pyrophosphate (TPP) has been considered as a potential biomarker for Alzheimer's disease (AD) based on several clinical reports that apparently lower blood TPP levels were found in patients with mild cognitive impairment to AD. However, highly sensitive and high-throughput detection of TPP in biological fluids remains an analytical challenge. Here, we report engineering RNA-based sensors to quantitatively measure TPP concentrations in whole blood samples with a detection limit down to a few nM. By fusing a TPP-specific aptamer with the hammerhead ribozyme for in vitro selection, we isolated an allosteric ribozyme with an EC50 value (68 nM) similar to the aptamer's KD value (50 nM) for TPP, which for the first time demonstrates the possibility to maintain the effector binding affinity of the aptamer in such engineered allosteric RNA constructs. Meanwhile, we developed a new blood sample preparation protocol to be compatible with RNA. By coupling the TPP-induced ribozyme cleavage event with isothermal amplification, we achieved fluorescence monitoring of whole blood TPP levels through the "mix-and-read" operation with high-throughput potential. We expect that the engineered TPP-sensing RNAs will facilitate clinical research on AD as well as other thiamine-related diseases.

BackgroundThiamine diphosphate (TDP) reduction plays an important role in cerebral glucose hypometabolism, the neurodegenerative indicator, in Alzheimer’s disease (AD). The mechanism underlying TDP reduction remains elusive. Thus, it is critical to define the mechanism and its effect on neurodegeneration, the pathological basis of the disease occurrence and progression.MethodsThe mRNA levels of all known genes associated with thiamine metabolism, including thiamine pyrophosphokinase (TPK), Solute Carrier Family 19 Member 2 (SLC19A2), SLC19A3, and SLC25A19, in brain samples of patients with AD and other neurodegenerative disorders in multiple independent datasets were analyzed. TPK protein levels were further examined in the brain tissues of AD patients and control subjects. A mouse model with conditional knockout (cKO) of TPK gene in the excitatory neurons of adult brain was established.ResultsThe brain TPK mRNA level was markedly lower in AD patients, but not in other neurodegenerative disorders. The brain TPK protein level was also significantly decreased in AD patients. TPK gene knockout in the mice caused cerebral glucose hypometabolism, β-amyloid deposition, Tau hyperphosphorylation, neuroinflammation, and neuronal loss and brain atrophy. Cross-species correlation analysis revealed the similar changes of gene profiling between the cKO mice and AD patients.ConclusionsThe deficiency of brain TPK, a key enzyme for TDP synthesis, is specific to AD. The cKO mice show AD-associated phenotypes and could serve as a new mouse model for AD studies. Our study provides a novel insight into the critical role of TPK in AD pathogenesis and its potential for the disease treatment.

Introduction We aimed to evaluate whether neuromelanin-sensitive MRI (NM-MRI) features in the substantia nigra pars compacta (SNc) were of diagnostic value to differentiate untreated essential tremor (ET) from de novo tremor-dominant Parkinson's disease (PDT). Methods Eighteen untreated ET patients, 21 de novo PDT patients and 21 healthy control subjects were recruited. All the subjects underwent clinical examination, motor and cognitive evaluations, as well as NM-MRI. High signal intensity of the lateral, central and medial SNc subregions on NM-MRI were evaluated using the width, signal intensity (contrast-to-noise ratio, CNR) and visual analysis. Diagnostic test performance of SNc values was investigated by using receiver operating characteristic analysis and net reclassification improvement (NRI). Results The width and CNR values of the lateral and central SNc subregions in PDT were significantly decreased compared with those in ET and control group. Using visual analysis, the total visual score of all SNc subregions was significantly reduced in PDT when compared with ET and control group. The width of the lateral SNc subregion allowed the best differentiation between ET and PDT, and visual analysis also showed good diagnostic value. NRI result indicated that visual analysis and the width of the lateral SNc subregion had the same diagnostic power. Conclusions The neuromelanin changes of SNc in ET and PDT follow the different patterns. Both the measurements and visual analysis of SNc on NM-MRI provide high diagnostic accuracy for differentiating ET from PDT subtype. NM-MRI is a potential tool in diagnostic work-up of tremor disorders.

Alzheimer's disease (AD) has been a devastating neurodegenerative disorder and lacks effective treatment to improve the prognosis for patients. Symptomatic treatment for AD mainly includes two categories: Acetylcholinesterase inhibitors and the N-methyl-d-aspartate (NMDA) receptor antagonist (memantine). They cannot significantly improve the quality of life and extend survival time for AD patients. Worse, almost all clinical trials for disease-modifying drugs have failed, and the reduction of brain β-amyloid (Aβ) deposition by multiple approaches, including inhibitors of β- or γ-secretase, vaccines, and antibodies against Aβ deposition, was found to have little effect on AD progression. A new therapeutic strategy for AD is urgently needed. Parkinson's disease also is a neurodegenerative disease having no effective treatment for modifying the disease. Nevertheless, successful symptomatic treatment using the combined therapies of l-DOPA supplement and modulators of l-DOPA metabolism greatly improves the prognosis for PD patients; the average survival time of the patient has been extended from 3-4 years to 10-15 years although dopaminergic neurons are still progressively decreasing. This provides useful implications for AD therapeutic strategies. AD patients manifest global cognitive decline, prominently represented by memory deficit, especially in the early stages of the disease. Further, the degree of decreased cognitive abilities correlates with cholinergic dysfunction and the hypometabolism of glucose, the dominant energy fuel for brain. Thus, the amelioration of brain cholinergic function and brain energy metabolism may be effective treatment to improve cognitive abilities of AD patients. Here, we highlighted the explorations of symptomatic therapeutics through modulating brain cholinergic function and energy metabolism in AD.

Alzheimer's disease is the most common neurodegenerative disease, and has a high level of genetic heritability and population heterogeneity. In this study, we performed the whole-exome sequencing of Han Chinese patients with familial and/or early-onset Alzheimer's disease, followed by independent validation, imaging analysis and function characterization. We identified an exome-wide significant rare missense variant rs3792646 (p.K420Q) in the C7 gene in the discovery stage (P = 1.09 × 10−6, odds ratio = 7.853) and confirmed the association in different cohorts and a combined sample (1615 cases and 2832 controls, Pcombined = 2.99 × 10−7, odds ratio = 1.930). The risk allele was associated with decreased hippocampal volume and poorer working memory performance in early adulthood, thus resulting in an earlier age of disease onset. Overexpression of the mutant p.K420Q disturbed cell viability, immune activation and β-amyloid processing. Electrophysiological analyses showed that the mutant p.K420Q impairs the inhibitory effect of wild type C7 on the excitatory synaptic transmission in pyramidal neurons. These findings suggested that C7 is a novel risk gene for Alzheimer's disease in Han Chinese.

Our previous studies proposed that Alzheimer's disease (AD) is a metabolic disorder and hypothesized that abnormal brain glucose metabolism inducing multiple pathophysiological cascades contributes to AD pathogenesis. Aging is one of the great significant risk factors for AD. Membrane aging is first prone to affect the function and structure of the brain by impairing glucose metabolism. We presume that risk factors of AD, including genetic factors (e.g., the apolipoprotein E ε4 allele and genetic mutations) and non-genetic factors (such as fat, diabetes, and cardiac failure) accelerate biomembrane aging and lead to the onset and development of the disease. In this review, we further modify our previous hypothesis to demonstrate "membrane aging" as an initial pathogenic factor that results in functional and structural alterations of membranes and, consequently, glucose hypometabolism and multiple pathophysiological cascades.

Thiamine is critical for cellular function, as its phosphorylated and active form, thiamine diphosphate (TDP), acts as coenzyme for three key enzymes in glucose metabolism. Mutations in thiamine transporter, TDP synthesizing enzyme or carrier, including solute carrier family 19 member 3 (SLC19A3), thiamine pyrophosphokinase (TPK1) and solute carrier family 25 member 19 (SLC25A19), have been associated with developmental neurological disorders, including microcephaly and Leigh syndrome. However, little is known about how thiamine metabolism regulates neuronal morphology at the cellular level. Here, using primary rat hippocampal neuronal cultures, we showed that reducing the expression of Tpk1, Slc25a19 or Slc19a3 in individual neurons significantly reduced dendrite complexity, as measured by total dendritic branch tip number (TDBTN) and total dendritic branch length (TDBL). The specificity of the RNAi effects were verified by overexpression of RNAi resistant human constructs. Importantly, changes in both TDBTN and TDBL tightly correlated with reduction in soma size, demonstrating coordinated regulation of soma and dendrite growth by thiamine. The requirement of thiamine metabolism for coordinated somata and dendrite growth is highly consistent with the microcephaly and neurodegenerative phenotypes observed in thiamine loss-of-function diseases.

Additional file 4: Figure 3B. B: HNMR result of precursor 5.

Additional file 14.

Additional file 8: Figure 3F. F: HNMR result of cold standard sample of 18F-deoxy-thiamine.

Additional file 6: Figure 3D. D: HNMR result of precursor 6.

Insulin-like growth factor-1 (IGF-1) shows protective effect against Aβ-induced cytotoxicity and apoptosis, but the underlying mechanisms are poorly characterized. The present study was conducted to explore the mechanisms involved in the beneficial effect of IGF-1 against Aβ-induced apoptosis in SH-SY5Y cells. We found that pretreatment with IGF-1 attenuated Aβ25-35-induced loss of cell viability and apoptosis in SH-SY5Y cells in a dose-dependent manner. In addition, IGF-1 inhibited the generation of reactive oxygen species (ROS) and increased the antioxidant activity in Aβ25-35-treated cells. Further, IGF-1 significantly promoted the nuclear translocation of Nrf2, and upregulated the expression of its downstream gene heme oxygenase-1 (HO-1). Moreover, LY294002, a specific PI3K inhibitor, was found to completely abolish the protective effect of IGF-1 on Aβ25-35-induced apoptosis and ROS generation. Together, our findings suggest that IGF-1 protects SH-SY5Y cells against Aβ25-35-induced cell injury by scavenging ROS via the PI3K/Akt-Nrf2 signaling pathway.

Differentiating early-stage Parkinson's disease (PD) from essential tremor (ET) remains challenging. In the current study, we aimed to evaluate whether visual analyses of neuromelanin-sensitive magnetic resonance imaging (NM-MRI) combined with nigrosome-1 (N1) imaging using quantitative susceptibility mapping (QSM) in the substantia nigra (SN) are of diagnostic value in the differentiation of de novo PD from untreated ET. Sixty-eight patients with de novo PD, 25 patients with untreated ET, and 34 control participants underwent NM-MRI and QSM. NM and N1 signals in the SN on MR images were visually evaluated using a 3-point ordinal scale. Receiver operating characteristic (ROC) analyses were performed to determine the diagnostic values of the visual ratings of NM and N1. The diagnostic values of the predicted probabilities were calculated via logistic regression analysis using the combination of NM and N1 visual ratings, as well as their quadratic items. The proportions of invisible NM and invisible N1 were significantly higher in the PD group than those in the ET and control groups (p < 0.001). The sensitivity/specificity for differentiating PD from ET was 0.882/0.800 for NM and 0.794/0.920 for N1, respectively. Combining the two biomarkers, the area under the curve (AUC) of the predicted probabilities was 0.935, and the sensitivity/specificity was 0.853/0.920 when the cutoff value was set to 0.704. Our findings demonstrate that visual analyses combing NM and N1 imaging in the SN may aid in differential diagnosis of PD and ET. Furthermore, our results suggest that patients with PD exhibit larger iron deposits in the SN than those with ET.

Iron metabolism dysfunction and redox-active iron-induced oxidative stress in the brain may contribute to the pathogenesis of Parkinson’s disease. We have previously demonstrated that reduced serum ceruloplasmin level exacerbates nigral iron deposition in Parkinson’s disease, although the underlying cause of the low serum ceruloplasmin level in Parkinson’s disease remains unknown. Fluorescent quantitative real-time polymerase chain reaction analysis revealed that patients with Parkinson’s disease had higher serum levels of microRNA (miR)-520d-5p than controls (p = 0.0011). Patients with Alzheimer’s disease or multiple system atrophy did not have significantly elevated miR-520d-5p levels. Expression of miR-520d-5p did not correlate with disease severity or the motor phenotype of Parkinson’s disease. Luciferase assays confirmed that miR-520d-5p was associated with ceruloplasmin gene expression, as predicted by the TargetScan tool and miRBase. In vitro experiments showed that miR-520d-5p reduced ceruloplasmin gene expression in the U251 astrocyte cell line. Our data suggest that miR-520d-5p may be a potential regulator of ceruloplasmin gene expression in vitro.

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 and its phosphate esters play vital physiological roles and thiamine deficiency causes deleterious effects on human body. It is important to quantify accurately the thiamine metabolites in body fluids. However, due to the lack of appropriate internal standards, poor inter-laboratory standardization and time-consuming pretreatment procedure, the existing methods are limited in clinical applications. Hence, we developed a single-step HPLC-MS/MS method for accurate and precise measurement of thiamine and its phosphate esters in human whole blood. Whole blood samples were deproteinized and the supernatants were collected. The levels of thiamine diphosphate (TDP), thiamine monophosphate (TMP), and thiamine were determined by HPLC-MS/MS method after adding isotopic internal standards. The method was linear from 15.625-3.125-1.563 nmol/L to 1000-200-100 nmol/L for TDP-TMP-thiamine. The lower limit of quantification was 15.625-3.125-1.563 nmol/L. The intra-day and inter-day precisions and accuracy for all QCs samples were ≤15.9% and ≤11.1%, respectively. The matrix effect was not significant. Recoveries were 103.7% for TDP, 102.7% for TMP, and 105.3% for thiamine. All QCs were stable for three freeze-thaw cycles, or at room temperature for 3 h, or at -80 °C for 15 days. We compared this new method with an established HPLC method based on derivatization of thiamine metabolites. It is found that this method correlated well with HPLC method for TDP determination (R2 = 0.93). However, the correlation was not ideal for TMP (R2 = 0.40) or thiamine (R2 = 0.72) determination. Subject's diet was shown to have no significant effect on the concentrations of thiamine metabolites in their blood samples. To conclude, we developed a single-step, non-derivatization HPLC-MS/MS method that can detect thiamine and its phosphate esters in human whole blood accurately and quickly.

Figure S1. Blood TDP levels do not significantly correlate with brain glucose metabolism in control subjects. Figure S2. Blood TMP and thiamine levels do not significantly correlate with brain amyloid deposits in patients with AD. Figure S3. Blood and brain TDP levels do not significantly correlate with brain glucose metabolism in control mice. Figure S4. Blood TMP and thiamine levels do not significantly correlate with brain amyloid deposits in patients with AD. (PDF 454 kb)

Our previous studies have demonstrated that ceruloplasmin (CP) dysmetabolism is correlated with Parkinson's disease (PD). However, the causes of decreased serum CP levels in PD patients remain to be clarified. This study aimed to explore the potential association between genetic variants of the CP gene and PD. Clinical features, serum CP levels, and the CP gene (both promoter and coding regions) were analyzed in 60 PD patients and 50 controls. A luciferase reporter system was used to investigate the function of promoter single-nucleotide polymorphisms (SNPs). High-density comparative genomic hybridization microarrays were also used to detect large-scale copy-number variations in CP and an additional 47 genes involved in PD and/or copper/iron metabolism. The frequencies of eight SNPs (one intronic SNP and seven promoter SNPs of the CP gene) and their haplotypes were significantly different between PD patients, especially those with lowered serum CP levels, and controls. However, the luciferase reporter system revealed no significant effect of the risk haplotype on promoter activity of the CP gene. Neither these SNPs nor their haplotypes were correlated with the Hoehn and Yahr staging of PD. The results of this study suggest that common genetic variants of CP are associated with PD and further investigation is needed to explore their functions in PD.

Background The 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. Methods Positron 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. Results FDG 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. Conclusions We 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. Electronic supplementary material The online version of this article (10.1186/s13195-018-0354-2) contains supplementary material, which is available to authorized users.

Introduction The cause of low serum ceruloplasmin levels in Parkinson's 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.

Growing evidence has indicated that iron deposition in the substantia nigra (SN) 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.

BACKGROUNDThiamine metabolites and activities of thiamine-dependent enzymes are impaired in Alzheimer's disease (AD).OBJECTIVETo clarify the mechanism for the reduction of thiamine diphosphate (TDP), an active form of thiamine and critical coenzyme of glucose metabolism, in AD.METHODSForty-five AD patients clinically diagnosed and 38 age- and gender-matched control subjects without dementia were voluntarily recruited. The contents of blood TDP, thiamine monophosphate (TMP), and thiamine, as well as the activities of thiamine diphosphatase (TDPase), thiamine monophosphatase (TMPase), and thiamine pyrophosphokinase (TPK), were assayed by high performance liquid chromatography.RESULTSBlood TDP contents of AD patients were significantly lower than those in control subjects (79.03 ± 23.24 vs. 127.60 ± 22.65 nmol/L, P 0.05). Blood TDP levels correlated negatively with TDPase activities (r = -0.2576, P = 0.0187) and positively with TPK activities (r = 0.2426, P = 0.0271) in all participants.CONCLUSIONEnhanced TDPase and TMPase activities may contribute to the reduction of TDP level in AD patients. The results imply that an imbalance of phosphorylation-dephosphorylation related to thiamine and glucose metabolism may be a potential target for AD prevention and therapy.

Aim: We evaluated the diagnostic value of blood thiamine metabolites for Alzheimer’s disease (AD) by using positron emission tomography with 11C-Pittsburgh compound B (11C-PiB PET) scanning. Methods: Thirty-eight clinically diagnosed AD patients were voluntarily recruited. Blood thiamine metabolites were measured by high-performance liquid chromatography. All the patients received 11C-PiB PET scanning for the measurement of cerebral amyloid deposition. Results: Thiamine diphosphate (TDP) had 66.7% sensitivity and 80.0% specificity for AD diagnosis, while the γ-value representing the best combination of thiamine metabolites and age had 24.2% sensitivity and 100.0% specificity according to the cut-off value of our previous study. Conclusion: Blood TDP but not γ-value exhibited results significant for AD diagnosis., Lay abstract: In this study, we investigated the diagnostic value of blood thiamine metabolites for Alzheimer’s disease as examined by positron emission tomography with 11C-Pittsburgh compound B scanning. Our results suggest that the reduction of blood thiamine diphosphate may be a stable biomarker useful for Alzheimer's disease diagnosis.

To date, we still lack disease-modifying therapies for Alzheimer's disease (AD). Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine (300 mg daily) over 18 months. All patients were examined by positron emission tomography with Pittsburgh compound B (PiB-PET) and exhibited positive imaging with β-amyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improvement as assayed by the Mini-Mental Status Examination (MMSE) with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain compared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Our study provides new insight to the development of disease-modifying therapy.