Characterization Of Profiles And Severity Of AMCI Based On Neuropsychological Tests And Structural Brain MRI

SECTION 1Characteristics of neuropsychological profiles of patients with aMCI and the exploratory grading of aMCI according to cognitive domains sufferedObjective:To determine the neuropsychological profiles in patients with amnestic mild cognitive impairment (aMCI) with comprehensive neuropsychological tests battery and to grade the severity of cognitive decline. Methods:Thorough cognitive investigations of general intelligence, memory, language, attention and executive function as well as visuo-spatial function plus social functions were performed on 214 patients with aMCI and 230 cognitively normal controls. A comprehensive neuropsychological battery that included memory, language, attention, executive function and visuo-spatial ability was used. The tests were as follows:mini-mental status examination (MMSE), The Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), Clinical dementia rating scale (CDR), memory and executive screening scale(MES), Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), the Auditory Verbal Learning Test (AVLT), the Rey-Osterrieth Complex Figure Test (CFT), the Boston Naming Test (BNT; the 30-item version), the Animal Fluency Test (AFT), the Symbol Digit Modalities Test(SDMT), the Trail Making Test-A and B (TMT-A, TMT-B), the Stroop Color-Word Test (SCWT), the Clock-drawing test, and Center for Epidemiologic Studies Depression scale (CESD). The patients were tested by a skilled rater and then divided into different groups according to the number of cognitive domains that failed. Pairwise comparisons were conducted to build up the optimal subgroups. Memory process as illustrated by AVLT measures were compared on the basis of the previously obtained classification. Also we carried out the correlation tests between screening tools for aMCI and the specific measures employed in the battery. Results:Firstly we found that the majority of aMCI patients presented in the memory clinic suffered cognitive decline in multiple domains with the prominence of memory complaints. Of the 214 aMCI patients only less than 15% were purely amnestic MCI, as high as 70% patients were insidiouly suffering from malfunction of 2-4 cognitive domains. Episodic delayed recall especially that of AVLT and LMT is a sensitive measure for memory loss. However visuo-spatial ability declining often gives a clue as impairment of at least 4 domains.2. a-MCI patients were allocated into three groups assumed to be of different severity with cognitive impairment of two or less domains as mild or stage 1, five domains as severe or stage 3, and those in between as moderate or stage 2. Significant difference in memory measures exists among the 3 groups or stages.3. The learning-retention curve from AVLT measures varies a great deal between aMCI patients and cognitively normal controls with that leaning slope flattened and forgetting slope sharpened. AVLT-SDR is significantly less than AVLT-LDR. AVLT-CR does not improve over AVLT-LDR. The curve neglects group*trial interaction among 3 groups. The false positives in AVLT-REC increase along with the severity of illness. Conclusion:aMCI patients presented to the memory clinic often suffer from multiple impairments and a thorough investigation of cognitive is warranted. The classification of aMCI into different severity groups in accordance with the number of domains affected is a viable option. Patients with aMCI suffering different numbers of domains vary in the memory process.SECTION 2Impact on the neuropsychological functions of polymorphism of APOE gene in patients with aMCIObjective:To ascertain the difference of polymorphism of APOE gene in patients with aMCI, AD and normal controls and to investigate the impact on the neuropsychological functions of polymorphism of APOE gene in patients with aMCI Methods:This is a cross-sectional case-control study. Participants included 214 patients with aMCI, 201 with sporadic AD and 205 normal controls (NC).Genotyping on APOE gene with TaqMan(?)-MGB probe was performed. Comparisons of the frequency of APOE genotype and alleles were conducted in the above-mentioned 3 groups. The comparisons were carried out among the 3 different groups of aMCI as well. Independent T test to ascertain the difference between ε4(+) group and ε4(-) group as well as between ε2(+) group and s2(-)group. Results:There are significant difference of the frequency of APOE s4 between NC and aMCI, aMCI and AD, AD and NC (P<0.01) while with regards to ε2 the difference between aMCI and NC was non-significant(P=0.868).2. No significant difference in APOE genotype or alleles was detected among the 3 groups of aMCI.3. APOE ε4 carriers significantly differed from noncarriers only on those indices for memory. And this applies to ε2 carrier status. Alleles ε2 and ε4 probably target different memory stage to be functional. Conclusion:The frequency of APOE gene intervened that of AD and normal controls while no significant difference exists among 3 groups of aMCI. APOE ε4 and ε2 alleles modulate cognitive function through the impact of memory.SECTION 3Whole-brain voxel-based morphometry of grey matter in amnestic mild cognitive impairmentObjective:To investigate the mode of change of cortical volume from three-dimensional T1-weighted MR image among aMCI patients with increasing cognitive domains using VBM8 and DARTEL toolbox. Methods:A total of 160 patients with aMCI underwent brain imaging with routine sequences plus 3D inversion-recovery-based T1WI (magnetization-prepared rapid acquisition with gradient-echo (T1WI-3D-MPRAGE). The data were transferred to PC, then preprocessed with spm8 toolbox-vbm8 and updates with DARTEL technique employed for image normalization. Correlation analysis was carried out between the volumes of GM, WM, CSF and total generated through the above-mentioned segmentation procedure and clinical variables or neuropsychological measures. The volume was also compared on the clinical severity basis. Whole-brain voxel-based morphometry of grey matter was conducted using pairwise comparison with T test from spm8 among the three different groups. Results:Cognitive measures reflecting general cognition such as MMSE, ADAS-cog, CDR sum of boxes and MES together with social function index-ADCS-ADL were significantly correlated with the proportion of grey matter (P<0.01). Memory indices such as several of the AVLT measures were correlated with grey matter proportion, too. Attention and executive function measures were significantly correlated with the proportion of grey matter and that of white matter (P<0.05). Attention measures were also correlated with the volume of grey matter and white matter (P<0.05).2. Significant difference in white matter volume as well as its proportion was detected among the 3 groups of aMCI. 3. The volume of the bilateral hippocampus, parahippocampal gyrus, amygdala (right side more atrophy), anterior cingulate gyrus, subcallosal gyrus, rectus gyrus, medial frontal gyrus, supplementary motor area and Brodmann 24 area in moderate to severe groups of aMCI patients combined was significantly smaller than that in the mild aMCI group (P< 0.05, FDR corrected, K>100 voxels), but the mild aMCI group showed no area with more atrophy than the combined group. Pairwise comparison between mild and moderate group or moderate versus severe group or mild versus severe group, while not significant using FDR correction for multiple comparison provide us with a rough knowledge of progressive atropy with increasing domains. Conclusion:VBM can detect subtle brain volume changes with the increase of domains suffered in aMCI. Areas with brain atrophy are expanding as the cognitive domains impaired increase in numbers.