Correlation Between Cerebral Glucose Metabolism And The Levels Of Blood Thiamine Metabolites In Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized pathologically by β-amyloid deposition, neurofibrillary tangles (NFTs), synaptic and neuronal loss.Glucose metabolic disorder in brain is one of important features in AD. The studies for subjects with risk genes (APOE ε4, PS1) have demonstrated a significant reduction of cerebral glucose and energy metabolism, which precedes the onset of clinical symptoms for decades. The researches on enzyme activities associated with glucose and energy metabolism in the temporal cortex showed the significant reduction of thiamine-dependent enzymes activity, including pyruvate dehydrogenase complex (PDH), α-ketoglutarate dehydrogenase complex (KGDH) and transketolase. Since three key enzymes were encoded by different genes, it could be difficult to explain this phenomenon by genetic mutations. However, thiamine diphosphate, the active form of thiamine, is the common coenzyme of these enzymes. The pathological damages caused by chronic thiamine deficiency were similar to those of AD, such as selective neuronal loss and abnormal phosphorylation of tau protein in brain. Our previous studies have found that benfotiamine could improve the memory abilities, hippocampal neurogenesis in senile mice and reduce Aβ deposition and tau hyperphosphorylation in APP/PS1 transgenic mouse model.Therefore, we hypothesize that thiamine mal-metabolism may reduce cerebral enzymes activities of PDH, KGDH and transketolase in AD patients. Abnormal metabolism of thiamine may play an important role in development of AD through perturbing glucose and energy metabolism. However, to date, no study reports the relation between blood thiamine metabolism and cerebral glucose metabolism. In this study, we detected blood thiamine level by high performance liquid chromatography, evaluated cerebral glucose metabolism through FDG-PET, and finally, investigated the relationship between blood thiamine metabolite measurement and cerebral glucose metabolism.Part 1 The assessment of whole blood thiamine metabolite levels in patients with Alzheimer’s DiseaseObjective:To detect the levels of blood thiamine metabolites in AD patients and control subjects.Methods:In total 13 AD patients diagnosed according to DSM IV and 17 normal control subjects were enrolle. The subjects with digestive diseases and recent thiamine supplement were excluded. All subjects were assessed with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR) and Activity of Daily Living (ADL). The levels of thiamine and its derivatives were separated by a reversed-phase HPLC column and measured by fluoroscope. All subjects were also tested for hemoglobin, fasting blood glucose, liver and kidney function, thyroid function, folic acid and vitamin B12.Results:1. Compared with the control group, the blood total thiamine and TDP levels in AD patients significantly decreased, and TMP level increased (Total Thiamine:103.9±7.7 vs.127.7±3.9 nmol/L, P<0.01:TDP:84.9±7.1 vs.115.1±4.0 nmol/L, P<0.001; TMP: 16.1±2.2 vs.9.5±1.0 nmol/L, P<0.01). There was no significantly difference in blood thiamine level between the AD and control group (Thiamine:2.9±0.7 vs.3.1±0.4 nmol/L, P>0.05).2. In patients with AD, the levels of total thiamine, TDP, TMP, and thiamine showed no obvious correlations with the scores of MMSE, MoCA, ADL, IADL, tADL and CDR.Conclusion:1. The abnormality of blood thiamine metbolism was observed in AD.2. The levels of blood total thiamine, TDP, TMP, thiamine showed no obvious correlations with the severity in AD patients.Part 2 Cerebral glucose metabolism in patients with Alzheimer DiseaseObjective:To evaluate the cerebral glucose metabolism state in patients with Alzheimer DiseaseMethods:The cerebral glucose metabolism states in all subjects were successfully assessed with 18F-FDG PET/CT after they were injected with 18F-FDG. The mean and maximum values of FDG uptake in related brain regions were taken using software package PMOD and data were analyzed with SPSS 19.0.Results:1. Compared with control group, AD group showed significantly lower rates of brain glucose metabolism in bilateral temporal lobe(ALL 81,82,83,84,85,86,87,88,89, 90), bilateral Parietal(ALL 59,60,61,62,63,64,65,66), hippocampus(ALL 37,38), parahippocampal gyrus (ALL 39,40), Posterior cingulate(ALL 35,36), and precuneus (ALL 67,68).2. Somatic motor and sensory cortex was not affected obviously in AD patients.Conclusion:AD group showed significantly lower rates of cerebral glucose metabolism in bilateral temporal, lobe bilateral parietal, hippocampus, parahippocampal gyrus, posterior cingulate, and precuneus while somatic motor and sensory cortex was not affected obviously.Part 3 The relationship between the levels of blood thiamine metabolites and cerebral glucose metabolism in patients in Alzheimer DiseaseObjective:To explore the relationship between the levels of blood thiamine metabolites and cerebral glucose metabolism in AD patients. Methods:The levels of blood thiamine and its derivatives were measured by HPLC and the cerebral glucose metabolism state of AD patients were successfully assessed with 18F-FDG PET/CT. The relationship between the levels of blood thiamine metabolites and the rates of cerebral glucose metabolism in ROIs of AD patients and normal control subjects were analyzed with SPSS 19.0.Results:1. Blood TDP levels in AD patients showed obvious correlation with cerebral regional average rates of glucose metabolism in several ROIs (parietal lobe (superior parietal gyrus, supramarginal gyrus), temporal lobe (superior temporal gyrus, middle temporal gyrus) and (middle frontal gyrus, opercular part inferior frontal gyrus, triangular part inferior frontal gyrus, orbital part inferior frontal gyrus)). (0.3247<r2<0.4512, P<0.05)2. Blood total thiamine levels in AD patients showed obvious correlation with cerebral regional average rates of glucose metabolism in several ROIs (parietal lobe (supramarginal gyrus, superior parietal gyrus, inferior parietal margin of the angular gyrus), temporal lobe (superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus) and (middle frontal gyrus, opercular part inferior frontal gyrus, triangular part inferior frontal gyrus, orbital part inferior frontal gyrus)). (0.3652≤r2≤0.5922, P<0.05)3. Blood TDP levels in AD patients showed obvious correlation with cerebral regional max rates of glucose metabolism in several ROIs (parietal lobe (superior parietal gyrus, inferior parietal, but supramarginal and angular gyri), temporal lobe (superior temporal gyrus, temporal pole:superior temporal gyrus, middle temporal gyrus) and (middle frontal gyrus, opercular part inferior frontal gyrus, orbital part inferior frontal gyrus)). (0.3189≤r2≤0.6065, P<0.05)4. Blood total thiamine levels in AD patients showed obvious correlation with cerebral regional max rates of glucose metabolism in several ROIs (parietal lobe (superior parietal gyrus; inferior parietal, but supramarginal and angular gyri; angular gyrus), temporal lobe (superior temporal gyrus, temporal pole:superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus) and (middle frontal gyrus, opercular part inferior frontal gyrus, orbital part inferior frontal gyrus)). (0.3443<r2<0.6859, P<0.05)5. Blood TDP and total thiamine levels in control subjects showed no obvious correlation with cerebral regional average rates of glucose metabolism in the whole brain, except for that the average rates of glucose metabolism of medial superior frontal gyrus of the left brain (ALL23) had obvious correlation with blood TDP level.6. Blood TDP and total thiamine levels in control group showed no obvious correlation with cerebral regional max rates of glucose metabolism in the whole brain.Conclusion:1. Obvious correlations between brain average/max regional glucose metabolism and blood thiamine levels in several ROIs were found in AD group. Brain regional glucose metabolism would decrease as the blood thiamine metabolite levels decreased. The changes in TDP-dependent process may play a vital role in decreased cerebral glucose metabolism in AD patients.2. No obvious correlation between brain glucose metabolism and blood thiamine level was found in control group.