Analysis Of The Relationship Between Total Plasma Homocysteine And Neurodegeneration Like AD And Cognition Function

Background:Alzheimer’s disease which is the most common cause of dementia in the elderly,is a chronic degenerative disease of the central nervous system.Its clinical feature is cognitive dysfunction,accompanied by mental symptoms and behavioral disorders.In recent years,it has been found that the increase of plasma total homocysteine（t Hcy）can affect cognitive function and is an independent risk factor of AD,which can double the risk of AD,its mechanism may be related to neurodegenerative changes.The main pathological features of AD are senile plaques formed byβ-amyloid protein deposition,neuronal fibrillary tangles formed by high phosphorylation aggregation of tau protein,and apoptosis and loss of neuronal synapses and cholinergic neurons.In the imaging aspect,the atrophy of hippocampus,temporal lobe,inner olfactory and other structures can be seen.The decrease of Aβ₄₂,the increase of total tau（t-tau）and p-tau₁₈₁ in cerebrospinal fluid were the core biomarkers of AD,which were closely related to the pathological changes of AD.Objective:Our objective was to investigate whether hyper plasma total homocysteine（t Hcy）influences core biomarkers of neurodegeneration of and cognition.Methods:583 participants who detect plasma total homocysteine were selected from the Alzheimer’s Disease Neuroimaging Initiative with diagnoses of mild cognitive impairment and normal cognition.As t Hcy>10.8μmol/L was the cut-off,participants were divided into two groups:hyper t Hcy group（222 cases）and normal group（361 cases）.Multivariate linear regression model and mixed linear model were used to study the associations of hyper t Hcy with brain atrophy,CSF levels of Aβ42,t-tau and p-tau₁₈₁,and cognition.Analyses were performed across and within cognitive diagnostic strata.Using R 3.5.1software to analyze the data,using R 3.5.1 and Graph Pad Prism 7.00 software to make images.Results:Age,male ratio and hypertension ratio in hyper t Hcy group were significantly higher than those in normal group,while MMSE score was lower than those in normal group（P<0.05）.After adjusting for age,sex,education,APOE?4 status,cognitive diagnosis and total intracranial volume or cerebrospinal fluid volume,hyper t Hcy was associated with lower volume of middle temporal lobe（β=-800.8000,P=0.0004）,not the volumes of hippocampus and entorhinal.Hyper t Hcy was associated with greater CSF total tau（β=0.1160,P=0.0354）,not the levels of CSF Aβ₄₂ and p-tau₁₈₁.The association between hyper t Hcy and volume of middle temporal lobe was attenuated by 15%by the inclusion of CSF total tau.In cognitive function,hyper t Hcy was correlated with executive function score（β=-0.1403,P=0.0218）,not with memory summary score.After 12 months follow-up,Hyper t Hcy was only associated with the middle temporal lobe atrophy（β=-713.5470,P=0.0033）and increased t-tau protein level（β=11.6687,P=0.0440）.Conclusions:Hyper tHcy was closely related to the atrophy of middle temporal lobe and the increase of t-tau level in cerebrospinal fluid.In cross-sectional analysis,the correlation between hyper t Hcy and the volume of middle temporal lobe decreased by 15%due to the correction of t-tau.In terms of cognition,hyper t Hcy was associated with lower executive function scores.Therefore,hyper t Hcy may promote neurodegeneration of AD,and its effect may be related to the elevation of t-tau level in cerebrospinal fluid.