Identification of diagnostic biomarkers in Alzheimer's disease by integrated bioinformatic analysis and machine learning strategies.

Background: Alzheimer's disease (AD) is the most prevalent form of dementia, and is becoming one of the most burdening and lethal diseases. More useful biomarkers for diagnosing AD and reflecting the disease progression are in need and of significance. Methods: The integrated bioinformatic analysis combined with machine-learning strategies was applied for exploring crucial functional pathways and identifying diagnostic biomarkers of AD. Four datasets (GSE5281, GSE131617, GSE48350, and GSE84422) with samples of AD frontal cortex are integrated as experimental datasets, and another two datasets (GSE33000 and GSE44772) with samples of AD frontal cortex were used to perform validation analyses. Functional Correlation enrichment analyses were conducted based on Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Reactome database to reveal AD-associated biological functions and key pathways. Four models were employed to screen the potential diagnostic biomarkers, including one bioinformatic analysis of Weighted gene co-expression network analysis (WGCNA)and three machine-learning algorithms: Least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) analysis. The correlation analysis was performed to explore the correlation between the identified biomarkers with CDR scores and Braak staging. Results: The pathways of the immune response and oxidative stress were identified as playing a crucial role during AD. Thioredoxin interacting protein (TXNIP), early growth response 1 (EGR1), and insulin-like growth factor binding protein 5 (IGFBP5) were screened as diagnostic markers of AD. The diagnostic efficacy of TXNIP, EGR1, and IGFBP5 was validated with corresponding AUCs of 0.857, 0.888, and 0.856 in dataset GSE33000, 0.867, 0.909, and 0.841 in dataset GSE44770. And the AUCs of the combination of these three biomarkers as a diagnostic tool for AD were 0.954 and 0.938 in the two verification datasets. Conclusion: The pathways of immune response and oxidative stress can play a crucial role in the pathogenesis of AD. TXNIP, EGR1, and IGFBP5 are useful biomarkers for diagnosing AD and their mRNA level may reflect the development of the disease by correlation with the CDR scores and Breaking staging.

Identification of biomarkers differentiating Alzheimer's disease from other neurodegenerative diseases by integrated bioinformatic analysis and machine-learning strategies.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease, imposing huge mental and economic burdens on patients and society. The specific molecular pathway(s) and biomarker(s) that distinguish AD from other neurodegenerative diseases and reflect the disease progression are still not well studied. Methods: Four frontal cortical datasets of AD were integrated to conduct differentially expressed genes (DEGs) and functional gene enrichment analyses. The transcriptional changes after the integrated frontal cortical datasets subtracting the cerebellar dataset of AD were further compared with frontal cortical datasets of frontotemporal dementia and Huntingdon's disease to identify AD-frontal-associated gene expression. Integrated bioinformatic analysis and machine-learning strategies were applied for screening and determining diagnostic biomarkers, which were further validated in another two frontal cortical datasets of AD by receiver operating characteristic (ROC) curves. Results: Six hundred and twenty-six DEGs were identified as AD frontal associated, including 580 downregulated genes and 46 upregulated genes. The functional enrichment analysis revealed that immune response and oxidative stress were enriched in AD patients. Decorin (DCN) and regulator of G protein signaling 1 (RGS1) were screened as diagnostic biomarkers in distinguishing AD from frontotemporal dementia and Huntingdon's disease of AD. The diagnostic effects of DCN and RGS1 for AD were further validated in another two datasets of AD: the areas under the curve (AUCs) reached 0.8148 and 0.8262 in GSE33000, and 0.8595 and 0.8675 in GSE44770. There was a better value for AD diagnosis when combining performances of DCN and RGS1 with the AUCs of 0.863 and 0.869. Further, DCN mRNA level was correlated to CDR (Clinical Dementia Rating scale) score (r = 0.5066, p = 0.0058) and Braak staging (r = 0.3348, p = 0.0549). Conclusion: DCN and RGS1 associated with the immune response may be useful biomarkers for diagnosing AD and distinguishing the disease from frontotemporal dementia and Huntingdon's disease. DCN mRNA level reflects the development of the disease.

Physiological Roles of ß-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology.

The physiological functions of endogenous amyloid-ß (Aß), 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 Aß, particularly in regulating synaptic transmission, and the possible mechanisms, in order to decipher the real characters of Aß under both physiological and pathological conditions. Some worthy studies have shown that the deprivation of endogenous Aß 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 Aß in AD pathophysiology from the perspective of physiological meaning.

The Dynamic SUMOylation Changes and Their Potential Role in the Senescence of APOE4 Mice.

The ε4 allele of apolipoprotein E (APOE4) and aging are the major risk factors for Alzheimer's disease (AD). SUMOylation is intimately linked to the development of AD and the aging process. However, the SUMOylation status in APOE4 mice has not been uncovered. In this study, we investigated SENP1 and SUMOylation changes in the brains of aged APOE3 and APOE4 mice, aiming to understand their potential impact on mitochondrial metabolism and their contribution to cellular senescence in APOE4 mice. Concurrently, SUMO1-conjugated protein levels decreased, while SUMO2/3-conjugated protein levels increased relatively with the aging of APOE4 mice. This suggests that the equilibrium between the SUMOylation and deSUMOylation processes may be associated with senescence and longevity. Our findings highlight the significant roles of SENP1 and SUMOylation changes in APOE4-driven pathology and the aging process.

Sleep Duration Positively Correlates with Global Cognition in the Non-Demented Older Adults with High School or above Education.

BACKGROUND: Sleep disturbance is common in the elderly. The effect of sleep duration on cognitive function in the non-demented older adults with high school or above education needs to be clarified. Here, we conducted a cross-sectional study to explore the correlation between sleep duration and multi-domain cognitive function in non-demented older adults. METHODS: A total of 226 adults aged 60 years and over who have an educational background over 9 years, received a battery of neuropsychological evaluations. The Mini-Mental State Examination (MMSE) was used to assess global cognitive function, the Auditory Verbal Learning Test (AVLT), Verbal Fluent Test (VFT), Trial Making Test-A/B (TMT-A/B), Symbol Digit Modalities Test (SDMT), and Rey-Osterriech Complex Figure Test (CFT) were used to assess the memory, language, attention and executive, and visuospatial functions respectively. Sleep characteristics were collected by questionnaire. RESULTS: Subjects with sleep disturbance performed worse in visuospatial ability as compared with those with normal sleep. A significant correlation between nocturnal/total sleep duration and MMSE scores and CFT scores was found in overall subjects using linear regression models after adjusting for age, gender, education and BMI. Consistently, the nocturnal/total sleep duration positively correlated with MMSE scores after controlling for age, gender, education, BMI, hypertension, diabetes, hyperlipidemia, coronary artery disease and household conditions. CONCLUSIONS: The results indicate that shorter sleep duration impairs the global cognition and visuospatial ability in the older adults with high school or above education, even in the very early non-demented stage.

Association Between Blood Biochemical Factors Contributing to Cognitive Decline and B Vitamins in Patients With Alzheimer's Disease.

Background: Malnutrition, metabolism stress, inflammation, peripheral organs dysfunction, and B vitamins deficiency significantly contribute to the progression and mortality of Alzheimer's disease (AD). However, it is unclear which blood biochemical indicators are most closely related to cognitive decline and B vitamins deficiency (thiamine, folate, vitamin B12) in patients with AD. Methods: This was a cross-sectional study of 206 AD patients recruited from six hospitals in China. Thiamine diphosphate (TDP), the bioactive form of thiamine, was measured by high-performance liquid chromatography fluoroscopy (HPLC) at a single center. Levels of biochemical indicators (except TDP) were measured by regular and standard laboratory tests in each hospital. Pearson's rank correlation analysis was used to assess relationships between B vitamins and biochemical indicators. T-test was used to compare the difference between ApoE ε4 and non-ApoE ε4 groups. Differences were considered statistically significant as P < 0.05. Results: Among the biochemical results, in AD population, malnutrition indicators (erythrocyte, hemoglobin, serum albumin, and total protein) were most significantly associated with cognitive function, as was free triiodothyronine (FT3) levels which had been observed in previous study. Malnutrition and FT3 levels depend on age but not apolipoprotein E (ApoE) genotype. Meanwhile, Among the B vitamins, TDP was the most significantly associated with malnutrition indicators and FT3. Conclusion: Our results indicated that TDP reduction could be a modifiable risk factor for malnutrition and FT3 that contributed to cognitive decline in AD patients. Correcting thiamine metabolism could serve as an optional therapy target for AD treatment.

The impact of thiamine deficiency and benfotiamine treatment on Nod-like receptor protein-3 inflammasome in microglia.

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.

Dynamic Change of Intracellular Metabolism of Microglia Evaluated by Transcriptomics in an Alzheimer's Mouse Model.

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-ß deposition.

A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status.

BACKGROUND: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer's disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. METHODS: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. RESULTS: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = - 0.985, p = 0.015). CONCLUSION: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

Beneficial effects of low-dose lithium on cognitive ability and pathological alteration of Alzheimer's disease transgenic mice model.

Lithium has been shown to delay the progression of Alzheimer's disease to reduce the prevalence of dementia. However, its narrow therapeutic index and numerous toxic effects at conventional dosage limited its long-term use to older subjects. Here, we tested the effect of low-dose lithium on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mouse. We found that both chronic and acute administration of lithium dose-dependently increased in blood and brain tissues. Long-term administration of low-dose lithium does not affect the body weight of APP/PS1 mice, but can significantly improve spatial memory of APP/PS1 mice. Pathologically, it also reduced ß-amyloid plague and p-tau levels. Therefore, our results show that long-term low-dose lithium can ameliorate cognitive dysfunction and pathological alterations of Alzheimer's disease transgenic mice, and provide a theoretical basis for the further application of low-dose lithium in Alzheimer's disease clinical treatment.

Multilayered N-Glycoproteome Profiling Reveals Highly Heterogeneous and Dysregulated Protein N-Glycosylation Related to Alzheimer's Disease.

Protein N-glycosylation is ubiquitous in the brain and is closely related to cognition and memory. Alzheimer's disease (AD) is a multifactorial disorder that lacks a clear pathogenesis and treatment. Aberrant N-glycosylation has been suggested to be involved in AD pathology. However, the systematic variations in protein N-glycosylation and their roles in AD have not been thoroughly investigated due to technical challenges. Here, we applied multilayered N-glycoproteomics to quantify the global protein expression levels, N-glycosylation sites, N-glycans, and site-specific N-glycopeptides in AD (APP/PS1 transgenic) and wild-type mouse brains. The N-glycoproteomic landscape exhibited highly complex site-specific heterogeneity in AD mouse brains. The generally dysregulated N-glycosylation in AD, which involved proteins such as glutamate receptors as well as fucosylated and oligomannose glycans, were explored by quantitative analyses. Furthermore, functional studies revealed the crucial effects of N-glycosylation on proteins and neurons. Our work provides a systematic multilayered N-glycoproteomic strategy for AD and can be applied to diverse biological systems.

Decreased Function of Delayed Recall in Non-demented Elderly Subjects With Apolipoprotein E ε4 Allele.

Apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Inconsistent results about the role of APOE ε4 alleles on cognitive decline of community non-dementia elderly have been reported. This study aimed to examine the relationship between APOE ε4 allele and cognitive abilities in the subjects aged 60 years or above from a community in Shanghai, China. A total of 1445 participants voluntarily accepted the analysis of APOE genotype and global cognitive assay using the Mini Mental Status Evaluation (MMSE). There were no significant differences in total MMSE scores between APOE ε4 carriers and non-carriers. In addition, the performances of orientation, registration, attention, calculation, and language had no significant differences between subjects with and without APOE ε4 allele. However, stratified analysis showed that the performance of delayed recall in subjects with APOE ε4 allele was inferior to that in non-ε4 carriers (p = 0.041). Further, the multiple linear regression analysis showed the significant correlations between the presence of APOE ε4 allele and the scores of the delayed memory subdomain if age, gender, and education were adjusted but no significant correlations if the related factors were not adjusted. The results indicate that significant impact of APOE ε4 allele only on the delay memory but not on global or other sub-domains of cognitive abilities.

Thiamine deficiency contributes to synapse and neural circuit defects.

BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.

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

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.

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-ß (Aß) 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 Aß 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.

Thiamine deficiency contributes to synapse and neural circuit defects

BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.

Thiamine metabolism is critical for regulating correlated growth of dendrite arbors and neuronal somata.

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.

Enhanced Activities of Blood Thiamine Diphosphatase and Monophosphatase in Alzheimer's Disease.

BACKGROUND: Thiamine metabolites and activities of thiamine-dependent enzymes are impaired in Alzheimer's disease (AD). OBJECTIVE: To clarify the mechanism for the reduction of thiamine diphosphate (TDP), an active form of thiamine and critical coenzyme of glucose metabolism, in AD. METHODS: Forty-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. RESULTS: Blood 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<0.0001). Activities of TDPase and TMPase were significantly enhanced in AD patients than those in control subjects (TDPase: 1.24 ± 0.08 vs. 1.00 ± 0.04, P < 0.05; TMPase: 1.22 ± 0.04 vs. 1.00 ± 0.06, P < 0.01). TPK activity remained unchanged in AD as compared with that in control (0.93 ± 0.04 vs. 1.00 ± 0.04, 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. CONCLUSION: Enhanced 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.

Measurement of Blood Thiamine Metabolites for Alzheimer's Disease Diagnosis.

BACKGROUND: Brain glucose hypometabolism is an invariant feature and has significant diagnostic value for Alzheimer's disease. Thiamine diphosphate (TDP) is a critical coenzyme for glucose metabolism and significantly reduced in brain and blood samples of patients with Alzheimer's 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.