Olfactory identification and apolipoprotein E epsilon 4 allele in mild cognitive impairment

To investigate olfactory identification and apolipoprotein E ε4 allele in patients with mild cognitive impairment (MCI), we used Cross-Cultural Smell Identification Test (CC-SIT) from University of Pennsylvania to assess olfactory identification performance and polymerase chain reaction (PCR) to detect apolipoprotein E ε4 (ApoE ε4) allele in 28 patients with MCI and the 30 age-matched control subjects in present study. The Mann-Whitney U test demonstrated that the MCI group performed significantly worse on CC-SIT than the normal aging group (P<0.01). For MCI patients olfaction scores correlated positively with CAMCOG-C (r=0.61, P<0.01), but not with age, gender or years of education. In normal subjects, the CC-SIT score showed no significant associations with age, gender, years of education, or CAMCOG-C. As the least common allele in Chinese, ε4 was found in 13.3% of controls and in 35.8% of MCI in this study. ApoE ε4 was significantly higher in MCI group than normal group (χ²=4.65, P<0.01). There was a significant effect of allele status on odor identification: subjects with ε4 allele were not able to identify as many odors as the subjects without ε4 allele (P<0.01). These results suggested that the decreased olfactory identification in MCI may be a marker for the early diagnosis of Alzheimer’s disease, and ApoE genotype may be part of the basis of olfactory identification decline.     

Associative recognition in mild cognitive impairment: Relationship to hippocampal volume and apolipoprotein E

Associative memory involves remembering relations between items of information and is critically dependent on the hippocampus, a brain structure that shows early changes in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease. We examined associative and item memory in aMCI with a focus on the role of medial-temporal lobe regions and genetic risk for Alzheimer's disease. Twenty-four individuals with aMCI and 21 demographically matched healthy older adults underwent associative recognition testing, structural brain imaging, and apolipoprotein E (ApoE) genotyping. A significant interaction between group and recognition type indicated poorer associative recognition than item recognition across tasks in the aMCI group relative to controls. Within the aMCI group, associative but not item recognition showed sizable and significant correlations with hippocampal volume (but not with other medial temporal-lobe structures) and with number of ApoE ε4 alleles. Correlations were smaller and generally not significant in the control group. Our findings replicate and extend previous studies by showing an associative recognition impairment in aMCI that is not accounted for by an item recognition deficit, is related to structural integrity of the hippocampus, and increases with genetic risk for Alzheimer's disease.     

The apolipoprotein E epsilon4 allele and incident Alzheimer's disease in persons with mild cognitive impairment

Possession of one or more copies of the apolipoprotein E (APOE) epsilon4 allele is a known risk factor for Alzheimer's disease (AD), but it is uncertain whether the epsilon4 allele is associated with disease incidence among persons with mild cognitive impairment (MCI). We addressed this issue with data from the Religious Orders Study. Participants were 181 older Catholic clergy members who met criteria for MCI based on a uniform structured clinical evaluation; 56 (30.9%) had at least one epsilon4 allele. Clinical evaluations, which included clinical classification of dementia and AD, were repeated annually. During a mean of 5.7 years of observation, 79 persons (43.6%) developed AD. In a proportional hazards model that controlled for age, sex, and education, possession of an epsilon4 allele was associated with a 93% increase in the risk of developing Alzheimer's disease (95% CI; 1.02, 2.63). There was a marginally significant reduction in the effect of epsilon4 in older compared to younger participants (p=.053). The results suggest that possession of an epsilon4 allele does increase risk of AD in persons with MCI.     

Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment

BACKGROUND: Memory declines more rapidly with age in apolipoprotein E (APOE) epsilon4 carriers than in APOE epsilon4 noncarriers, and APOE epsilon4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth. OBJECTIVE: To show that presymptomatic APOE epsilon4 homozygotes experience greater psychometric decline at a younger age than APOE epsilon4 heterozygotes and noncarriers before the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD). DESIGN: Prospective observational study SETTING: Academic medical center. PARTICIPANTS: A total of 43 APOE epsilon4 homozygotes, 59 APOE epsilon4 heterozygotes, and 112 APOE epsilon4 noncarriers aged 50 to 69 years were cognitively healthy and matched at entry according to age, educational level, and sex. INTERVENTION: Neuropsychological battery given every 2 years. MAIN OUTCOME MEASURES: Predefined test and cognitive domain decline criteria applied to consecutive epochs. RESULTS: Of 214 participants, 48 showed no decline on any test, 126 showed decline on only 1 test in 1 or more domains, and 40 showed decline on 2 or more tests in 1 or more domains. Cognitive domain decline occurred in 4 of 10 APOE epsilon4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE epsilon4 heterozygotes and noncarriers (7.6%) (P = .02) and was more predictive of subsequent decline than nondomain decline (17 of 24 [70.8%] vs 29 of 70 [41.4%]; P = .01). Decline on any memory test was predictive of further decline (P < .001), as was memory domain decline (P = .006) in all genetic subgroups. Seven participants developed MCI (in 6) or AD (in 1), of whom 5 were APOE epsilon4 homozygotes (P = .008). Retrospective comparison showed that those who experienced multidomain, memory, and language domain decline had lower spatial and memory scores at entry than those who experienced no decline. CONCLUSIONS: APOE epsilon4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE epsilon4 heterozygotes or noncarriers before the diagnosis of MCI and AD, thus confirming and characterizing the existence of a pre-MCI state in this genetic subset.     

Brain MRI hippocampal volume and prediction of clinical status in a mild cognitive impairment trial

Mild Cognitive Impairment (MCI) is considered a transitional stage in the pathogenesis of Alzheimer’s disease; however, not all MCI patients progress to clinically defined AD or decline at identical rates. Hippocampal atrophy, as measured by Magnetic Resonance Imaging (MRI), may be a marker for hippocampal pathology in patients with MCI and predict a more rapid deterioration to clinical AD. In this study, we used MRI data from an ongoing MCI clinical trial to determine whether MRI hippocampal volume at baseline was associated with cognitive and functional performance in MCI subjects and whether it predicted those individuals who were more likely to develop AD. We performed correlational analyses between the MRI hippocampal volumes at study entry and the subjects’ concurrent performance on neuropsychological measures and clinical ratings. Larger hippocampal volume was associated with better performance on tests of memory, general cognition, and overall clinical ratings. Further analyses suggested that a smaller baseline hippocampal volume may be associated with a higher risk of developing clinical AD. As the trial is still ongoing, these results require confirmation once the trial is completed. In summary, these data suggest that MRI hippocampal volume may be a useful correlate of disease severity in MCI subjects and a prognostic indicator of subsequent AD.     

Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment

OBJECTIVE: To test the hypothesis that MRI-based measurements of hippocampal volume are related to the risk of future conversion to Alzheimer's disease (AD) in older patients with a mild cognitive impairment (MCI). BACKGROUND: Patients who develop AD pass through a transitional state, which can be characterized as MCI. In some patients, however, MCI is a more benign condition, which may not progress to AD or may do so slowly. PATIENTS: Eighty consecutive patients who met criteria for the diagnosis of MCI were recruited from the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry. METHODS: At entry into the study, each patient received an MRI examination of the head, from which the volumes of both hippocampi were measured. Patients were followed longitudinally with approximately annual clinical/cognitive assessments. The primary endpoint was the crossover of individual MCI patients to the clinical diagnosis of AD during longitudinal clinical follow-up. RESULTS: During the period of longitudinal observation, which averaged 32.6 months, 27 of the 80 MCI patients became demented. Hippocampal atrophy at baseline was associated with crossover from MCI to AD (relative risk [RR], 0.69, p = 0.015). When hippocampal volume was entered into bivariate models-using age, postmenopausal estrogen replacement, standard neuropsychological tests, apolipoprotein E (APOE) genotype, history of ischemic heart disease, and hypertension-the RRs were not substantially different from that found univariately, and the associations between hippocampal volume and crossover remained significant. CONCLUSION: In older patients with MCI, hippocampal atrophy determined by premorbid MRI-based volume measurements is predictive of subsequent conversion to AD.     

Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E epsilon4 allele

Although apolipoprotein E epsilon4 is an established risk factor for Alzheimer's disease, its effect on the rate of progression of Alzheimer's disease remains unknown. The purpose of this longitudinal study was to elucidate whether the rate of hippocampal atrophy is a function of the apolipoprotein E genotypes and severity of disease. Fifty-five patients with probable Alzheimer's disease were the subjects. The annual rate of hippocampal atrophy was determined by using magnetic resonance imaging repeated at a 1-year interval. On a two-way analysis of variance, the effect of the apolipoprotein E epsilon4 allele on hippocampal atrophy was significant, but neither the effect of severity nor the interaction term was significant. In further analysis with one-way analysis of variance, the mean annual rate of hippocampal atrophy was significantly different between the groups of patients with (9.76 +/- 4.27%) and without the apolipoprotein E epsilon4 allele (6.99 +/- 4.24%). Apolipoprotein E epsilon4 dose was significantly correlated with the rate of hippocampal atrophy (rs = 0.277, Spearman rank correlation coefficient), suggesting a gene dose effect. The involvement of the apolipoprotein E epsilon4 allele in the progression of hippocampal atrophy has implications for therapeutic approaches in Alzheimer's disease and should be taken into consideration in longitudinal studies including clinical drug trials.     

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss

BackgroundA blood-based biomarker of Alzheimer's disease (AD) would be superior to cerebrospinal fluid (CSF) and neuroimaging measures in terms of cost, invasiveness, and feasibility for repeated measures. We previously reported that blood ceramides varied in relation to timing of memory impairment in a population-based study. The present objective was to examine whether plasma ceramides varied by AD severity in a well-characterized clinic sample and were associated with cognitive decline and hippocampal volume loss over 1 year.MethodsParticipants included 25 normal controls (NC), 17 amnestic Mild Cognitive Impairment (MCI), and 21 early probable AD. A thorough neuropsychological battery and neuroimaging with hippocampal volume determination were conducted at baseline and 1 year later. Plasma ceramides were assayed at baseline using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry.ResultsAlthough all saturated ceramides were lower in MCI compared with AD at baseline, ceramides C22:0 and C24:0 were significantly lower in the MCI group compared with both NC and AD groups (P < .01). Ceramide levels did not differ (P > .05) in AD versus NC. There were no cross-sectional associations between ceramides C22:0 and C24:0 and either cognitive performance or hippocampal volume among any group. However, among the MCI group, higher baseline ceramide C22:0 and C24:0 levels were predictive of cognitive decline and hippocampal volume loss 1 year later.ConclusionResults suggest that very long-chain plasma ceramides C22:0 and C24:0 are altered in MCI and predict memory loss and right hippocampal volume loss among subjects with MCI. These plasma ceramides may be early indicators of AD progression.     

轻度认知障碍和轻度Alzeimer病的海马体积MRI测量

目的研究轻度认知功能障碍（mildcognitiveimpairment,MCI）和轻度阿尔兹海默病（A1zheimerdisease,AD）患者的海马体积萎缩情况,评价利用影像学测定海马体积对MCI、AD的诊断价值。方法应用3．0T磁共振分别对20例MCI患者,20例轻度AD患者,20例认知功能正常的对照者的海马体积进行测量,所得数值用头颅体积进行标准化处理。采用计算机SPSS13．0统计学软件进行资料的统计学处理,比较三组之间体积的差异。结果对照组与MCI组,对照组与AD组的两侧海马体积均存在显著的统计学差异,轻度AD与MCI组两侧的海马体积无显著的统计学差异。结论认知功能障碍与海马体积具有一定的相关性,海马萎缩对早期认知障碍有一定的诊断意义。     

Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status.

OBJECTIVE: To determine whether olfactory status predicts cognitive decline (CD) over a 2-year follow-up period. METHODS: The authors enrolled individuals in a community-based longitudinal study of memory and aging in the Japanese-American community in King County, WA, between 1992 and 1994. At baseline they screened 1,985 persons using the Cognitive Abilities Screening Instrument (CASI) and the 12-item Cross-Cultural Smell Identification Test (CC-SIT). Of these 1,985 people, 1,836 were found not to be demented. Two years later the authors rescreened 1,604 participants with the CASI. They defined CD as a 2-year loss of > or =5.15 points/100 on the CASI. They genotyped 69% of the 1,604 people completing both examinations for apolipoprotein E (apoE). RESULTS: After adjusting for age, CASI score at baseline, education, smoking, sex, and follow-up time, the authors determined an odds ratio (OR) for CD of 0.90 (95% CI, 0.84 to 0.97) for an increase in each correct point on the CC-SIT (range, 0 to 12). Compared with normosmics, the OR for persons with impaired olfaction (microsmics) was 1.25 (95% CI, 0.83 to 1.89) and for anosmics the OR was 1.92 (95% CI, 1.06 to 3.47). Persons who were anosmic at baseline and who had at least one APOE-epsilon4 allele had 4.9 times the risk of CD (95% CI, 1.6 to 14.9) compared with normosmics without the epsilon4 allele. The estimated relative risk among women was 9.7 (95% CI, 1.3 to 70.4), and for men the risk was 3.2 (95% CI, 0.8 to 12.6). Receiver operating characteristic (ROC) curves showed that although the area under the curve (AUC) for baseline CASI was only 0.51, the AUC for CC-SIT alone was 0.62. Adding CC-SIT to the ROC model with CASI improved the AUC curve from 0.51 to 0.62. CONCLUSIONS: Unexplained olfactory dysfunction in the presence of one or more APOE-epsilon4 alleles is associated with a high risk of cognitive decline. Cross-Cultural Smell Identification Test classifies people with cognitive decline correctly to a greater degree than a global cognitive test.     

他汀类药物对不同载脂蛋白E基因型MCI患者认知功能的影响

目的:探讨statins(阿托伐他汀)对不同载脂蛋白E(ApoE)基因型的轻度认知障碍(MCl)患者认知功能的影响。方法:76例MCI患者按是否携带ApoEε4基因以及是否给予statins分为四组,比较1年前后的血脂水平及MMSE评分。结果:Statins可降低总胆固醇(TC)和低密度脂蛋白(LDL)水平。与不携带ApoEε4等位基因(ε4-)者比较,携带者(ε4+)应用statins治疗后血浆LDL水平显著降低(2.36±0.70比3.00±0.75,P相似文献   

Decreased cerebral blood flow velocity in apolipoprotein E ɛ4 allele carriers with mild cognitive impairment

The aim of this study was to investigate the changes in cerebral blood flow velocity (CBFV) and its relation to apolipoprotein E (apoE) ɛ 4 allele in mild cognitive impairment (MCI). Thirty MCI and 30 controls were assessed using Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination-Chinese version (CAMCOG-C), and then insonated in the anterior (ACA), middle (MCA) and basilar (BA) cerebral arteries using transcranial Doppler ultrasonography. Compared with controls, MCI showed significant decreases in the mean ( V _m), systolic ( V _s) and diastolic ( V _d) CBFV, bilaterally in MCA and ACA ( P  < 0.05–0.001), but not in BA. Compared with 17 apoE ɛ 4 allele non-carriers, 13 carriers in MCI showed significant CBFV decreases, bilaterally in MCA ( P  < 0.05–0.001). Our findings, the decreased CBFV in apoE ɛ 4 allele carriers with MCI, suggest that a large sample and longitudinal study in CBFV and cognitive changes may have the implications on early diagnosis of Alzheimer's disease.     

Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study

BACKGROUND: It remains unknown whether depression and apolipoprotein E genotype are risk factors for incident mild cognitive impairment (MCI). OBJECTIVE: To determine whether elderly individuals with depression (measured by the short Geriatric Depression Scale) are at increased risk of developing incident MCI. DESIGN: Prospective cohort study. SETTING: Primary care clinic. PARTICIPANTS: A cohort of 840 cognitively normal elderly subjects without depression at recruitment who were followed up prospectively for a median of 3.5 years (range, 0.4-12.8 years). Subjects who developed depression (score of >/=6 on the short Geriatric Depression Scale; depression cohort) were compared with all remaining subjects (referent cohort). MAIN OUTCOME MEASURES: Incidence of MCI (primary outcome) and incidence of MCI or dementia (composite secondary outcome). RESULTS: Individuals in the depression cohort were at significantly increased risk of subsequent incident MCI (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1) after adjusting for age (time scale), sex, and education, and considering dementia as a competing outcome. The association was stronger in men but did not vary by severity of depression. We observed a synergistic interaction between apolipoprotein E genotype (epsilon3/epsilon4 or epsilon4/epsilon4) and depression (joint effect HR, 5.1; 95% CI, 1.9-13.6; test for additive interaction, P = .03). We found a similar association between depression and the subsequent composite outcome of incident MCI or dementia (HR, 2.6; 95% CI, 1.6-4.3). CONCLUSIONS: Cognitively normal elderly individuals who develop depression are at increased risk of subsequent MCI. We found a synergistic interaction between depression and apolipoprotein E genotype.     

Three-dimensional patterns of hippocampal atrophy in mild cognitive impairment

OBJECTIVE: To measure hippocampal volumes in patients diagnosed as having subtypes of mild cognitive impairment (MCI) relative to those of elderly control subjects and those of patients with Alzheimer disease (AD) using 3-dimensional mesh reconstructions. DESIGN: A magnetic resonance imaging volumetric study of MCI subgroups (MCI, amnesic subtype [MCI-A]; and MCI, multiple cognitive domain subtype) using 3-dimensional mesh reconstructions of the structure. SETTING: Referral dementia clinic. SUBJECTS: Twenty-six subjects with MCI (MCI-A, n = 6; and MCI, multiple cognitive domain subtype, n = 20), 20 subjects with AD, and 20 controls who were equivalent in age, education, and sex distributions. MAIN OUTCOME MEASURES: Three-dimensional parametric mesh models of the hippocampus and total hippocampal volumes. RESULTS: The hippocampi of the patients with AD were significantly atrophic relative to those of the healthy controls. The MCI, multiple cognitive domain subtype, group did not differ from the controls, yet was significantly different from the MCI-A and the AD groups. The MCI-A patients had significant hippocampal atrophy compared with the controls, and did not differ significantly from the patients with AD. CONCLUSION: These data add to the growing evidence that there are multiple forms of MCI, that they have distinct neuropathological correlates, and that MCI, multiple cognitive domain subtype, is not a more advanced form of the MCI-A subtype.     

Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment

BACKGROUND: In cognitively impaired patients without dementia, the utility of apolipoprotein E (APOE) genotyping is unclear. OBJECTIVE: To evaluate the predictive utility of the APOE epsilon4 genotype for conversion to probable Alzheimer disease (AD). DESIGN: Naturalistic, longitudinal study. SETTING: Memory disorders outpatient clinic. PATIENTS: A total of 136 patients with memory complaints were determined to have mild cognitive impairment and were evaluated every 6 months. Fifty-seven age- and sex-matched healthy controls were evaluated annually. MAIN OUTCOME MEASURES: Primary outcome measures included conversion to AD. Secondary outcome measures included change over time in Mini-Mental State Examination (MMSE) score and Selective Reminding Test (SRT) delayed recall score. RESULTS: The APOE epsilon4 allele was present in 25% of patients and 21% of healthy controls. During a mean +/- SD follow-up of 35.2 +/- 24.3 months, 35 of 136 patients converted to AD. APOE epsilon4 carrier status did not differ between converters (31%) and nonconverters to AD (23%, P = .3) and did not affect the time trend in MMSE or SRT scores in the entire sample. Four of 5 APOE epsilon4 homozygotes converted to AD compared with 7 of 29 heterozygotes (P = .02). In a Cox proportional hazards model stratified by age quartiles, after controlling for sex, education, MMSE score, and SRT delayed recall score, APOE epsilon4 increased the risk of AD in patients 70 to 85 years old (n = 57; risk ratio, 2.77; 95% confidence interval, 1.1-7.3; P = .03) but not in patients 55 to 69 years old (n = 79; P = .7). CONCLUSIONS: APOE epsilon4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE epsilon4 homozygosity was associated with increased risk of conversion to AD. However, APOE epsilon4 carrier status by itself did not predict cognitive decline or conversion to AD, indicating that APOE genotyping in patients with mild cognitive impairment may have limited clinical applicability for prediction of outcome.     

1H magnetic resonance spectroscopy, cognitive function, and apolipoprotein E genotype in normal aging, mild cognitive impairment and Alzheimer's disease.

The aim of this study was to examine the associations of apolipoprotein E (APOE) genotype, metabolic changes in the posterior cingulate detected by 1H magnetic resonance spectroscopy (MRS), and neuropsychologic measures of memory and cognition both in normally aging elderly, and in patients with mild cognitive impairment (MCI) and AD. We studied 67 controls, 18 MCI and 33 AD patients. We used the Dementia Rating Scale total score (DRSTOT) as a measure of general cognitive function and the total learning from the Auditory Verbal Learning Test (AVTOT) as a measure of memory performance. No differences were noted on 1H-MRS metabolite ratios or cognitive measures across APOE genotype within control and patient groups. In controls, age was a significant predictor of both cognitive test scores, and NAA/Cr was a univariate associate of DRSTOT. All 3 1H-MRS metabolite ratios, N-acetylaspartate (NAA)/creatine (Cr), myoinositol (MI)/Cr, and NAA/MI, were univariate associates of AVTOT and DRSTOT scores in the combined MCI and AD group. In stepwise regression analyses in the combined patient group only NAA/MI entered the models. These data suggest NAA/Cr could be a modest predictor of general cognitive function in both healthy elderly and impaired patients, while MI/Cr is a more specific marker for neuropsychologic dysfunction associated with neurodegenerative disease. Among 1H-MRS measurements, the NAA/MI ratio maybe the most efficient predictor of memory and cognitive function in patients with MCI and AD.