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.

Central nervous system nocardiosis in a 54-year-old man with lateral ventricular choroid plexitis and diffused meningitis: A case report.

INTRODUCTION: Nocardiosis is an unusual infection caused by aerobic gram-positive bacteria in the genus Nocardia. Infections resulting from Nocardia species are frequent in immunosuppressive patients. Weakened immune systems caused by human immunodeficiency virus infection, diabetes, cancer, and other conditions such as chronic lung disease, renal failure, etc, are the main risk factors for nocardiosis. Central nervous system (CNS) nocardiosis has been reported to represent ~2% of all and to be present in 15% to 50% of patients with systemic infection. The patient in our case had an isolated CNS nocardiosis caused by Nocardia terpenica infection, a rare reclassified Nocardia pathogen of CNS nocardiosis. CASE: We here present a 54-year-old Chinese male with a fever and headache for 15 days who showed positive meningeal irritation signs. Magnetic resonance imaging showed the right trigone of the lateral ventricular choroid plexitis and diffused leptomeningeal meningitis involving the bilateral cerebral hemisphere, cerebellar hemisphere, and brain stem. The patient was quickly diagnosed with CNS Nocardia infection by next-generation sequencing within 48 hours after admission. Meanwhile, the diagnosis was validated by Nocardia-positive staining in cerebral spinal fluid culturing. The patient was given trimethoprim-sulfamethoxazole, and his symptoms recovered after 3 days. CONCLUSIONS: In this case, the clinical, radiological, and microbiological findings highlight the importance of suspecting Nocardia as the potential pathogen in patients with central nervous system inflammation of doubted immune incompetence. In addition, next-generation sequencing as an effective test is also highly recommended for suspicious CNS infection patients to perform a rapid diagnosis and treatment.

Autoimmune encephalitis with posterior reversible encephalopathy syndrome: A case report.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a neuroimaging-based syndrome and is associated with multifocal vasogenic cerebral edema. Patients with PRES frequently demonstrate headache, seizure, encephalopathy, altered mental function, visual loss and so on. We here report a patient who showed persistent neurologic deficits after PRES and was ultimately diagnosed with autoimmune encephalitis (AE). CASE SUMMARY: This case exhibits a rare imaging manifestation of anti-casper 2 encephalitis which was initially well-matched with PRES and associated vasogenic edema. CONCLUSION: AE should be further considered when the etiology, clinical manifestations, and course of PRES are atypical.

Hydroxyurea-induced membrane fluidity decreasing as a characterization of neuronal membrane aging in Alzheimer's disease.

Aging is one of the significant risk factors for Alzheimer's disease (AD). Therefore, this study aimed to propose a new hypothesis "membrane aging" as a critical pathogenesis of AD. The concept of "membrane aging" was reviewed, and the possible mechanisms of membrane aging as the primary culprit of AD were clarified. To further prove this hypothesis, a hydroxyurea-induced "membrane aging" model was established in vitro and in vivo. First, neuronal aging was validated by immunocytochemistry with age-related markers, and membrane aging phenotypes were confirmed. The alterations of membrane fluidity within APP/PS1 mice were re-proved by intracerebroventricular injection of hydroxyurea. Decreased membrane fluidity was found in vitro and in vivo, accompanied by increased total cholesterol concentration in neurons but decreased cholesterol levels within membrane fractions. The Aß level increased considerably after hydroxyurea treatment both in vitro and in vivo. DHA co-treatment ameliorated membrane aging phenotypes and Aß aggregation. The study revealed the AMP-activated protein kinase/acetyl CoA carboxylase/carnitine palmitoyl transferase 1 pathway involved in membrane aging processes. These results strongly supported the idea that membrane aging was a pathogenesis of AD and might serve as a new therapeutic target for AD.

Membrane Aging as the Real Culprit of Alzheimer's Disease: Modification of a Hypothesis.

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.

A single-step method for simultaneous quantification of thiamine and its phosphate esters in whole blood sample by ultra-performance liquid chromatography-mass spectrometry.

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.

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.