| Multiple sclerosis(MS)is an inflammatory,demyelinating and degenerative autoimmune disorder of the central nervous system(CNS).MS is one of the most common causes of chronic neurological disability in young adults,and patients typically present between the ages of 20-40 years.The disease is predominant in women,being more than 3 times more likely in women than men.Most patients will develop substantial disability in motor,sensory,or cognitive functioning,which creates an increasing burden for society to provide the additional care needed.Cognitive impairment is a major disabling feature of MS,affecting 40%to 70%of patients.Information processing speed,immediate and delayed recall or memory,executive function,attention,and visuospatial abilities are the most commonly affected functions in MS.MS is categorized into 4 distinct types,primarily based on its clinical course,which are characterized by increasing severity:(a)relapsing-remitting MS(RRMS),the most common form,affecting 85%-90%of all MS patients,which involves relapses followed by remission;(b)secondary progressive MS(SPMS),which develops over time following diagnosis of RRMS;(c)primary progressive MS(PPMS)affecting 8%-10%of patients,noted as gradual continuous neurologic deterioration;and(d)progressive relapsing MS(PRMS),the least common form(<5%),which is similar to PPMS but with overlapping relapses.A large body of research support the heterogeneity of cognitive deficits across different MS phenotypes,and of underlying pathophysiological mechanisms between relapsing and progressive stages of the disease.The pathological processes underlying cognitive disability in multiple sclerosis are complex,and include neuronal and glial changes with associated structural and metabolic abnormalities.Converging areas of research have shown that the inhibitory and excitatory amino acid neurotransmitters,gamma-aminobutyric acid(GABA)and glutamate,respectively,are implicated in the pathophysiology of multiple sclerosis.Proton magnetic resonance spectroscopy(1H MRS)is a powerful methodology that allows the direct detection of endogenous metabolites in the human body non-invasively in vivo.Preliminary 1H-MRS reports in patients with established multiple sclerosis have demonstrated that glutamate concentrations in brain regions tend to be abnormally low,and glutamate concentrations in the hippocampus and cingulate cortices have been linked to worse memory function in patients with RRMS.However,other MRS studies using different protocols and patients with different characteristics,have detected that glutamate in the thalamic and hippocampus are unaltered between multiple sclerosis patients and controls.Therefore,in vivo studies of glutamate with MRS is necessary,which will allow identification of changes in this neurotransmitter in the disease,and its relation with cognitive disability.However,conventional MRS imaging tool for GABA measurement in vivo has limited accuracy due to relatively low concentration and spectral overlap with stronger signals of total creatine,glutamate,and N-acetylasparate.Mescher-Garwood point resolved spectroscopy(MEGA-PRESS)is a spectral editing technique,two frequency-selective,Gaussian inversion pulses and spectral editing technique are applied to separate GABA from creatine at 3.02 ppm.MEGA-PRESS allows to detect GABA selectively and has been successfully applied in a number of neurologic and psychiatric disorders,as well as in healthy control subjects.A recent research using MEGA-PRESS has suggested that GABA concentrations in sensorimotor cortex are reduced in patients with progressive multiple sclerosis.However,to date there has been a paucity of studies exploring the changes of GABA levels in patients with RRMS,and research on correlation between GABA levels and cognitive function in RRMS seems to be limited.Therefore,in the first part of our study,the MEGA-PRESS editing technique was used to measure and compare the levels of GABA in the posterior cingulate cortex(PCC),medial pre-frontal cortex(mPFC)and left hippocampus in RRMS patients and healthy control subjects.We further investigated whether brain GABA levels correlate with performance on cognitive function in patients.In the second part,we would detect the glutamate levels in RRMS patients,and the correlation between glutamate levels and cognitive performance in patients.There are two parts for the study:Part Ⅰ.Reduced GABA levels correlate with cognitive impairment in patients with multiple sclerosisObjectivesGamma-aminobutyric acid(GABA)is the major inhibitory transmitter in the human brain.Ample evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of multiple sclerosis(MS).We sought to develop edited magnetic resonance spectroscopy(MRS),using the MEGA-PRESS sequence,to detect brain GABA levels in relapsing-remitting multiple sclerosis(RRMS)and investigate whether GABA levels are associated with cognitive function.Materials and Methods28 RRMS patients and 26 age-and gender-matched healthy controls underwent 3D T1-weighted imaging,T2-FLAIR imaging and MRS of the posterior cingulate cortex(PCC),the medial prefrontal cortex(mPFC)and left hippocampus using the"MEGA-Point Resolved Spectroscopy Sequence"(MEGA-PRESS).All the patients met the criteria for diagnosis of RRMS,and had no history of relapse and steroids treatment within the preceding 3 months.All scans were performed using a 3T scanner(Philips Achieva TX,Best,The Netherlands),equipped with an eight-channel phased-array head coil.As the GABA signal detected by MEGA-PRESS is known to contain contributions from both macromolecules and homocarnosine rather than pure GABA,the detected signal is referred to as GABA+ rather than GABA.The MEGA-PRESS MRS data were processed using ’Gannet’(GABA-MRS Analysis Tool)in Matlab with Gaussian curve fitting to the GABA+ peaks.Patients and controls were assessed using a range of cognitive tests.Verbal memory was assessed using the Rey Auditory Verbal Learning Test(RAVLT)for immediate and delayed recall.The Trail-making test(TMT)was used to assess executive function.The Symbol-Digit Modalities Test(SDMT)was used to assess information processing speed.Visuospatial function was assessed using the Rey-Osterrich complex figure test(RCFT).Attention was assessed using the Stroop color word interference test(Stroop).The raw scores on cognitive tests were standardized(z-transformed).Statistical analyses were carried out using the statistical package SPSS 17.0.The threshold for significance was p<0.05.We tested the differences of GABA+between patients and controls by using an analysis of covariance(ANCOVA)with age as a covariate.Correlations between GABA+ and neuropsychological scores in RRMS were tested using the Pearson correlation coefficients(r).ResultsCompared with healthy controls,patients showed reduced GABA+ in the PCC(F = 4.655,p = 0.036)and left hippocampus(F = 4.504,p = 0.039).No statistical difference in GABA+ in the mPFC was seen between groups(F= 0.88,p = 0.353).In patients with RRMS,significant positive correlations were observed between verbal memory and GABA+ concentrations in the left hippocampus(RAVLT-total immediate recall:r = 0.477,p = 0.01;RAVLT-delayed recall:r = 0.471,p = 0.011;RAVLT-total scores:r = 0.451,p = 0.016).There was also a significant negative association between TMT scores and GABA+ concentrations in the PCC(r =-0.452,p = 0.016).Although these correlations have differing mathematical polarity,they all follow the same direction with lower GABA levels corresponding to more abnormal cognitive scores.No significant correlations between cognitive scores and GABA+were found in the mPFC.ConclusionDecreased GABA+ levels were present in the PCC and left hippocampus of patients with RRMS,and the GABA+ levels were related to cognitive impairment.This study demonstrates that GABAergic system abnormalities may be present in the RRMS pathogenesis,and provides imaging marker for the neurochemical mechanism of cognitive impairment in RRMS.Part Ⅱ.Glutamate levels correlate with cognition in patients with multiple sclerosisObjectivesTo investigate if brain glutamate levels in patients with relapsing-remitting multiple sclerosis(RRMS)are abnormal compared with healthy controls,and their relationship to cognitive function in RRMS.Materials and Methods20 RRMS patients and 25 age-and gender-matched healthy controls underwent 3D T1-weighted imaging,T2-FLAIR imaging and MRS on a 3 T scanner(Philips Achieva TX,Best,The Netherlands)with an eight-channel phased-array head coil.All the patients met the criteria for diagnosis of RRMS,and had no history of relapse and steroids treatment within the preceding 3 months.MRS were acquired from three brain regions:posterior cingulate cortex(PCC),medial prefrontal cortex(mPFC)and left hippocampus,using the PRESS sequence.LCModel was used to estimate the MRS data,with emphasis on the concentrations of glutamate.All subjects also underwent a cognitive assessment,and methods were the same with part-one study.Cognitive tests included the Symbol-Digit Modalities Test(SDMT),Trail-making test(TMT),Rey Auditory Verbal Learning Test(RAVLT),Rey-Osterrich complex figure test(RCFT)and Stroop color word interference test(Stroop).The raw scores on cognitive tests were standardized(z-transformed).Statistical analyses were carried out using the statistical package SPSS 17.0.The threshold for significance was p<0.05.Between-group glutamate levels comparison used an analysis of covariance(ANCOVA)with age as a covariate.Correlations between glutamate levels and neuropsychological scores in RRMS were tested using the Pearson correlation coefficients(r).ResultsPatients showed reduced glutamate in the left hippocampus(F = 5.300,p =0.026)compared with healthy controls.No significant differences were observed in glutamate concentrations in the PCC(F-2.209,p = 0.145)and mPFC(F = 1.238,p=0.272)between patients and controls.In patients with RRMS,significant positive correlations were observed between verbal memory and glutamate concentrations in the left hippocampus(RAVLT-total immediate recall:r = 0.511,p = 0.021;RAVLT-delayed recall:r = 0.539,p= 0.014;RAVLT-total scores:r = 0.614,p = 0.004).There was also a significant positive association between RCFT scores and glutamate concentrations in the mPFC(r =0.534,p = 0.015).No significant correlations were found between glutamate concentrations in the PCC and any of the cognitive tests.ConclusionIn conclusion,we found decreased glutamate levels in the left hippocampus region of patients with RRMS when compared with healthy controls.Glutamate levels in the left hippocampus and mPFC were associated with cognitive performance in patients.These findings reveal the glutamatergic system dysfunction in RRMS patients,supporting evidence to understand the pathogenesis of RRMS. |
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