The Pathophysiological Mechanisms And Early Diagnosis In Mild Cognitive Impairment

Mild cognitive impairment(MCI),which is a notion recently described in the field of aging and dementia,is currently thought of as a transition phase between healthy cognitive aging and Alzheimer's disease(AD) or other dementias.Investigation and recognition of MCI offer possibilities for potential treatment with the aim of delaying the onset or preventing AD and other dementias.Using multimodal studies-involving neuropsychological testing,transcranial Doppler ultrasonography(TCD) monitoring, molecular biology techniques,structural neuroimaging techniques,and psychophysical methods,we studied the pathophysiological mechanisms in MCI and searched for the biomarkers toward early diagnosis and treatment of AD or other dementias.AD and other dementias are accompanied by reduced cerebral blood flow(CBF). This decline in CBF can be the result of reduced metabolic need associated with neuronal damage as well as the restricted blood flow that results from vascular risk factors or/and vascular amyloidosis.Reduced CBF or regional cerebral hypoperfusion has been reported to be one of the early clinical manifestations in AD and may initiate a cascade of pathophysiological events that play an important role in the progression of AD.Apolipoprotein E(apoE) e4 allele is a well-known susceptibility genetic factor for sporadic and familial AD,and a number of studies have showed that apoE e4 carriers in MCI have much risk in developing AD.The aim of in this study was to evaluate the characteristics of cognitive impairment,resting cerebral blood flow velocity(CBFV) changes,apoE e4 allele frequency,to investigate the relations between apoE e4 and cognitive function,CBFV values,and to explore the correlations between cognitive impairment and CBFV changes in MCI.Thirty subjects with MCI and 30 controls were assessed using the Mini-Mental State Examination(MMSE),Cambridge Cognitive Examination-Chinese version(CAMCOG-C),and Geriatric Depression Scale(GDS). MCI and controls were then insonated at rest in the anterior(ACA),the middle(MCA) and the basilar(BA) cerebral arteries using TCD.Meanwhile,we used polymerase chain reaction- restriction fragment length polymorphism(PCR-RFLP) to detect the apoE genotypes and calculate the allele frequencies in all subjects.We found that there were significant differences between MCI and controls regarding MMSE,CAMCOG-C and its subscales(memory,language,praxis,attention and orientation)(P＜0.05～0.001).Compared with controls,MCI showed significant decreases in the mean(Vm),systolic(Vs) and diastolic(Vd) CBFV,bilaterally in the MCA and the ACA(P＜0.05～0.001),but not in the BA(P＞0.05).As the least common allele in Chinese,the apoE e4 allele frequencies were found in 23.33%of MCI and in 6.67%of controls,which were significantly higher in MCI than in controls(P＜0.05). Compared with 17 apoE e4 non-carriers,13 apoE e4 carriers in MCI showed significant decreases in CAMCOG-C(P＜0.01),MMSE,"memory","praxis" and "abstract thinking"(P＜0.05).There were significant differences between apoE e4 carriers and non-carriers in Vm,Vs and Vd,bilaterally in the MCA(P＜0.05～0.001) except for Vs of MCA-L(P=0.058).No significant differences of Vm,Vs and Vd in the ACA and BA (P＞0.05) were found.MMSE and CAMCOG-C in MCI decreased with the decline respectively in CBFVs of ACA-R(r=0.410,P=0.037) and CBFVm of MCA-L(r=0.425, P=0.030).The "memory" on CAMCOG-C correlated positively to CBFVs of MCA-R (r=0.600,P=0.001),while both the item "language" and "orientation" were associated positively with CBFVs of ACA-R(r=0.477,P=0.014;r=0.610,P=0.001;respectively).Our results show that MCI subjects have significant heterogeneity of cognitive impairment not only in the presentation of memory,but also in multiple cognitive domains-including language,attention,praxis,orientation,etc.The decreased CBFV, which is companied with the impairment cognition and especially affected by apoE e4 allele in MCI,indicates reduced CBF or regional cerebral hypoperfusion in the early phase of dementia.Through correlation analysis,we confirm that the cognitive impairments are associated with CBFV decline in MCI group.If a large sample and follow-up study confirms our findings,the TCD techniques could allow an objective assessment of the perfusion state in MCI.In future,CBFV may be regard as the marker which reveals the pathophysiological mechanisms in MCI.The combination of CBFV, neuropsychological testing,and apoE e4 allele may have the implications on early diagnosis of AD and other dementias.Leukoaraiosis(LA) is the neuroimaging term introduced recently by Hachinski et al.It has been described not only in vascular dementia(VaD) or vascular cognitive impairment(VCI) but also in neurodegeneration including AD and MCI,even in healthy aged people.To investigate the cognitive impairment and associated factors of AD/MCI with LA,we analyzed 25 AD/MCI with LA(leukoaraiosis with cognitive impairment,LA-CI) and 21 LA without cognitive impairment(LA-NCI).Data from neuropsychological testing including MMSE,CAMCOG,and GDS,vascular risk factors(VRFs) and structural neuroimaging were analyzed.Results showed that there were significant differences between AD/MCI with LA (LA-CI) and LA-NCI in tests that evaluate "language"(especially "language expression"),"memory" and "perception"(P＜0.01).AD/MCI with LA showed poorer performance in the tests evaluating "orientation","remote and recent memory", "attention","praxis" and "abstract thinking"(P＜0.05).No significant differences in the tests evaluating "learning memory","language comprehension" and "calculation" were found between two groups(P＞0.05).There were no significant differences in age,sex, body mass index(BMI),VRFs and depression symptoms between two groups(P＞0.05), while the educational level(P＜0.01),the grades of LA(P＜0.001),and the presence of lacunar infarcts(P＜0.01) had an effect on the cognitive functions in AD/MCI with LA. Compared with LA-NCI,AD/MCI with LA suffer with multiple domains of cognitive impairment,which involve in "language","memory","orientation","praxis","abstract thinking","attention",and "perception".The cognitive impairments in AD/MCI with LA are associated with the lower educational level,the higher grade of LA and the presence of lacunar infarcts.We suppose that vascular and degenerational mechanisms may co-contribute to pathology and the cognitive impairment in AD/MCI with LA.The visual function is closely associated with the superior cognitive function in human being.Visual dysfunction can hinder information processing at multiple levels and may explain aspects of cognitive function decline in aging and dementia.The visuospatial disorientation and impaired visual function may have the potential to affect the quality of life,including walking and automobile driving,in the early phase of AD. To investigate the impaired visual function,we studied 9 individuals with MCI and 9 normal aging individuals(NA) on a battery of tests designed to measure multiple aspects of complex visual function,including paracentral spatial contrast sensitivity (SCS),first-order and second-order motion perception.In the meanwhile,all subjects performed on the same cognitive test batteries(MMSE and CAMCOG-C).We found significant differences in paracentral SCS between MCI and NA (P＜0.001),which were affected chiefly in middle or high spatial frequencies.MCI had significantly higher thresholds of first-order motion perception(P＜0.001) and lower percentages of correct response of second-order motion perception(P＜0.001) than NA subjects.MCI appears to be a heterogeneous state in the percentages of correct response of second-order motion perception.There were significant negative correlations between age and paracentral SCS(r=-0.521,P=0.026),the percentages of correct response of second-order motion perception(r=-0.598,P=0.009).There were significant positive correlations between the percentages of correct response of second-order motion perception and CAMCOG-C(r=0.534,P=0.022),"praxis" (r=0.566,P=0.014),"abstract thinking"(r=0.488,P=0.040),and "perception" (r=0.512,P=0.030).No significant correlations were found between age and thresholds of first-order motion perception and between thresholds of first-order motion perception and MMSE,CAMCOG-C and subscales.We conclude that visuospatial disorientation may company with complex visual dysfunction in the early phase of AD.Correlation analyses show strong relationships between visual and cognitive scores in MCI.Psychophysical methods could allow an objective assessment of the visual function,perhaps providing useful clues to early diagnosis and treatment for dementia.A large sample and longitudinally study remains for future investigation.