Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer's disease

Oxidative stress has been associated with normal aging and Alzheimer's disease (AD). However, little is known about oxidative stress in mild cognitive impairment (MCI) patients who present a high risk for developing AD. The aim of this study was to investigate plasma production of the lipid peroxidation marker, malonaldehyde (MDA) and to determine, in erythrocytes, the enzymatic antioxidant activity of catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) in 33 individuals with MCI, 29 with mild probable AD and 26 healthy aged subjects. GR/GPx activity ratio was calculated to better assess antioxidant defenses. The relationship between oxidative stress and cognitive performance was also evaluated by the Mini Mental State Examination (MMSE). AD patients showed higher MDA levels than both MCI and healthy elderly subjects. MCI subjects also exhibited higher MDA levels compared to controls. Catalase and GPx activity were similar in MCI and healthy individuals but higher in AD. GR activity was lower in MCI and AD patients than in healthy aged subjects. Additionally, GR/GPx ratio was higher in healthy aged subjects, intermediate in MCI and lower in AD patients. No differences in GST activity were detected among the groups. MMSE was negatively associated with MDA levels (r = -0.31, p = 0.028) and positively correlated with GR/GPx ratio in AD patients (r = 0.68, p < 0.001). MDA levels were also negatively correlated to GR/GPx ratio (r = -0.31, p = 0.029) in the AD group. These results suggest that high lipid peroxidation and decreased antioxidant defenses may be present early in cognitive disorders.     

Free copper and resting temporal EEG rhythms correlate across healthy, mild cognitive impairment, and Alzheimer's disease subjects.

OBJECTIVE: The present study tested the hypothesis that the serum copper abnormalities were correlated with alterations of resting electroencephalographic (EEG) rhythms across the continuum of healthy elderly (Hold), mild cognitive impairment (MCI), and AD subjects. METHODS: Resting eyes-closed EEG rhythms delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), beta 2 (20-30Hz), and gamma (30-40Hz), estimated by LORETA, were recorded in 17 Hold, 19 MCI, 27 AD- (MMSE< or =20), and 27 AD+ (MMSE20) individuals and correlated with copper biological variables. RESULTS: Across the continuum of Hold, MCI and AD subjects, alpha sources in parietal, occipital, and temporal areas were decreased, while the magnitude of the delta and theta EEG sources in parietal, occipital, and temporal areas was increased. The fraction of serum copper unbound to ceruloplasmin positively correlated with temporal and frontal delta sources, regardless of the effects of age, gender, and education. CONCLUSIONS: These results sustain the hypothesis of a toxic component of serum copper that is correlated with functional loss of AD, as revealed by EEG indexes. SIGNIFICANCE: The present study represents the first demonstration that the fraction of serum copper unbound to ceruloplasmin is correlated with cortical delta rhythms across Hold, MCI, and AD subjects, thus unveiling possible relationships among the biological parameter, advanced neurodegenerative processes, and synchronization mechanisms regulating the relative amplitude of selective EEG rhythms.     

Taste in mild cognitive impairment and Alzheimer’s disease

In this prospective study we investigated the quantitative and qualitative taste function of patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). 29 healthy, elderly subjects, 29 MCI and 30 AD patients were tested using a validated taste test, the “taste strips”. Additionally, odor identification, odor discrimination, odor threshold, the mini-mental state examination (MMSE) and Apo E epsilon 4 status were examined. Regarding taste, there was a significant reduction of total taste scores and also the score for individual tastes on either side of the tongue between controls and MCI/AD patients. There was no significant difference in the taste scores between MCI and AD patients. A taste test may be a useful procedure for differentiating between healthy subjects and patients with MCI/AD in a clinical context. For diagnosing MCI versus AD, further tests such as smell test, MMSE, Apo E epsilon 4 status, FDG-PET and MRI appear to be useful.     

Validation analysis of the Attention Questionnaire Scale

Screening tests that briefly measure early signs of cognitive dysfunction in Alzheimer's disease (AD) are lacking. We devised a new scale focused on early detecting cognitive dysfunction: the Attention Questionnaire Scale (AQS). We prospectively studied the AQS in 268 subjects with varying degrees of cognitive dysfunction and compared it with the Mini-Mental Status Examination (MMSE), digit span test, trail making test part B, letter cancellation test, Instrumental ADL, Geriatric Depression Scale, and Clinical Dementia Rating Scale. The internal consistency was excellent with the AQS (Cronbach's α = 0.945). There were significant differences in the overall AQS scores across varying degree of cognitive dysfunction (26.80 ± 3.43 in normal elderly, 20.78 ± 4.83 in patients with mild cognitive impairment (MCI), 19.01 ± 4.49 in early AD, 16.00 ± 5.03 in mild AD, and 12.02 ± 6.28 in moderate AD), and subjects with the early stage of cognitive dysfunction could be further distinguished using the AQS than MMSE. The area under the receiver operating characteristic curve was estimated to be 0.93 (95% confidence interval 0.89-0.97) in screening for normal elderly versus patients with MCI or various stages of AD. The AQS provides greater screening ability for early stage cognitive dysfunction, used not only as a screening tool but also an appropriate simple questionnaire.     

Decreased Levels of Circulating Adiponectin in Mild Cognitive Impairment and Alzheimer’s Disease

Adiponectin, an adipocytokine released by the adipose tissue and has important roles in the metabolic regulation and inflammatory control, may play an important roles in the physiopathology of psychiatric and neurodegenerative disorders. The aim of the present work was to evaluate adiponectin serum levels in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) as compared to cognitively healthy elders and to correlate these levels with clinical and cognitive parameters. We further evaluated whether circulating adiponectin levels could predict progression from MCI to Alzheimer’s disease upon follow-up. We recruited 157 subjects (41 with AD, 65 with MCI and 51 elderly controls) in the baseline assessment. Follow-up data were available for 54 subjects with MCI and 43 controls in whom we ascertained the conversion to AD and the progression of cognitive impairment. Adiponectin was assayed by sandwich ELISA. Serum levels of adiponectin were significantly lower in MCI and AD as compared to controls (p < 0.001). After controlling for age, educational level and APOE genotype, adiponectin levels remained significantly reduced in these groups (p < 0.001). Circulating adiponectin levels did not predict cognitive decline in the elderly controls (i.e., progression from normal cognition to MCI) or progression to Alzheimer’s disease in subjects with MCI. We conclude that lower levels of adiponectin were associated with cognitive dysfunction, though it did not predict additional cognitive decline and conversion to dementia in this cohort of elderly subjects. Decreased adiponectin may be a surrogate marker of the pathological process in AD, linking clinical comorbidities, inflammation and cognitive dysfunction.     

Differences in cortical thickness in healthy controls, subjects with mild cognitive impairment, and Alzheimer's disease patients: a longitudinal study

In this study, we analyzed differences in cortical thickness (CTH) between healthy controls (HC), subjects with stable mild cognitive impairment (S-MCI), progressive MCI (P-MCI), and Alzheimer's disease (AD), and assessed correlations between CHT and clinical disease severity, education, and apolipoprotein E4 (APOE) genotype. Automated CTH analysis was applied to baseline high-resolution structural MR images of 145 subjects with a maximum followup time of 7.4 years pooled from population-based study databases held in the University of Kuopio. Statistical differences in CTH between study groups and significant correlations between CTH and clinical and demographic factors were assessed and displayed on a cortical surface model. Compared to HC group (n = 26), the AD (n = 21) group displayed significantly reduced CTH in several areas of frontal and temporal cortices of the right hemisphere. Higher education and lower MMSE scores were correlated with reduced CTH in the AD group, whereas no significant correlation was found between CDR-SB scores or APOE genotype and CTH. The P-MCI group demonstrated significantly reduced CTH compared to S-MCI in frontal, temporal and parietal cortices even after statistically adjusting for all confounding variables. Ultimately, analysis of CTH can be used to detect cortical thinning in subjects with progressive MCI several years before conversion and clinical diagnosis of AD dementia, irrespective of their cognitive performance, education level, or APOE genotype.     

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.     

Anosognosia in very mild Alzheimer's disease but not in mild cognitive impairment

OBJECTIVE: To study awareness of cognitive dysfunction in patients with very mild Alzheimer's disease (AD) and subjects with mild cognitive impairment (MCI). METHODS: A complaint interview covering 13 cognitive domains was administered to 82 AD and 79 MCI patients and their caregivers. The patient groups were comparable according to age and education, and Mini Mental State Examination (MMSE) scores were > or =24 in all cases. The discrepancy between the patients' and caregivers' estimations of impairments was taken as a measure of anosognosia. RESULTS: Self-reports of cognitive difficulties were comparable for AD and MCI patients. However, while in comparison to caregivers MCI patients reported significantly more cognitive impairment (p < 0.05), AD patients complained significantly less cognitive dysfunctions (p < 0.001). CONCLUSIONS: While most MCI patients tend to overestimate cognitive deficits when compared to their caregiver's assessment, AD patients in early stages of disease underestimate cognitive dysfunctions. Anosognosia can thus be regarded as a characteristic symptom at a stage of very mild AD (MMSE > or =24) but not MCI. Accordingly, medical history even in mildly affected patients should always include information from both patient and caregiver.     

Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease

Neuropsychological deficits, such as poor episodic memory, are consistent features of mild cognitive impairment and also that of early stage of dementia. The aim of the present study was to detect cognitive dysfunction among patients with Alzheimer's disease or with mild cognitive impairment (MCI), which refers to a transitional state between the cognition of normal aeging and mild dementia regarded as a high-risk condition for the development of clinically probable Alzheimer's disease (AD). Computerized tests of memory, attention and executive functions were studied in groups of AD subjects (n=15) and MCI subjects (n=25). On all measures, the performance of the AD group was significantly weaker compared to healthy individuals or to the MCI group. The performance of both the AD and MCI patients in the Paired Associate Learning test was significantly impaired, which may suggest that MCI patients are already in the early stages of the disease.     

蒙特利尔认知评估量表在轻度认知功能障碍筛查中的应用

目的 探讨蒙特利尔认知评估量表(MoCA)在轻度认知功能障碍(MCI)患者筛查中的应用.方法 应用简易精神状态检查量表(MMSE)、MoCA对32例MCI患者和50例健康对照者进行神经心理评估,比较二者筛查MCI的效果.结果 以26分为分界值,MoCA筛查MCI的敏感性为96.87%、特异性为76%,MMSE筛查MCI的敏感性为56.25%、特异性为96%;MoCA中除抽象思维、地点定向两项外,其余各亚项的评分在MCI组和对照组间差异均有统计学意义(P＜0.05):MMSE中仅计算与注意力、延迟回忆两项在MCI组和对照组间差异有统计学意义(P＜0.05),其余各项差异均无统计学意义(P＞0.05).结论 MoCA为高敏感性的MCI筛查工具,能全面评估MCI患者的认知功能.且可用于筛查MMSE得分正常的MCI患者.     

Cholesterol, copper and Abeta in controls, MCI, AD and the AD cholesterol-lowering treatment trial (ADCLT)

Cholesterol clearly plays an influential role in promoting the production of amyloid beta (Abeta) and possibly the progression of Alzheimer's Disease (AD). The AD Cholesterol-Lowering Treatment trial (ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N = 32) compared to placebo (N = 31). We assessed the circulating levels of Abeta(1-40), Abeta(1-42), ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Abeta levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Abeta(1-40) occurred in low- compared to high-function controls, with a further significant increase in MCI compared to low-function controls. Circulating Abeta(1-40) levels were decreased in AD compared to MCI. Levels of Abeta(1-42) were not significantly different between the groups. The slight gradual increase in circulating Abeta(1-40) and Abeta(1-42) levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support a role for cholesterol in AD and a possible influence of increasing circulating copper levels. The deterioration of function in controls and transition to MCI may be associated with concomitant incremental increases in circulating Abeta(1-40) levels. Increased cholesterol and ceruloplasmin levels may be associated with slight deterioration in function among controls as a precursor to impairment considered MCI. The clinical benefit of atorvastatin therapy is clearly not associated with decreased circulating Abeta or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration.     

上海市虹口区社区老年人轻度认知功能障碍的危险因素调查研究

目的 调查上海市虹口区社区居家模式老年人群轻度认知功能障碍（MCI）患者的危险因素。方法分为两步,第一步采用整群分层抽样的方法随机选取上海市虹口区4个街道社区,采用AD8简体中文版对社区卫生服务中心年度体检的≥65岁健康体检老年人进行评测,AD8≥2分为有认知功能障碍;第二步为完成第一步的认知功能障碍受试者,完成一般资料调查表、MMSE、MoCA等量表评测,进行临床诊断,以临床诊断的MCI患者作为研究对象,共163例,并随机选取健康照料者及体检健康人群127例作为健康对照组;采用Logistic回归分析筛查MCI患者的危险因素;组间比较采用秩和检验或t检验,计数资料采用卡方检验。结果第一步共8549名社区老年人完成评估;第二步有163例诊断为MCI,单因素logistic回归分析可见性别、年龄、教育年限、年收入、社会活动、锻炼、睡眠障碍与MCI的发生有关(P<0.05);多因素logistic回归分析表明女性、高龄、教育程度低、低年收入、缺少社会活动、缺少锻炼、睡眠障碍为虹口区社区居家模式MCI患者的高危因素。结论上海市虹口区社区老年人认知功能障碍的发病率较高,女性、高龄、教育程度低、低年收入、缺少社会活动、缺少锻炼、睡眠障碍是轻度认知功能障碍的主要危险因素。     

Subjective memory complaints with and without objective memory impairment: relationship with risk factors for dementia.

OBJECTIVE: The authors investigated the frequency distribution of well-established risk factors for dementia--high plasma homocysteine and the apolipoprotein E epsilon4 allele (APOE epsilon4)--among older women with subjective memory complaints (SMC) but no cognitive impairment, and with mild cognitive impairment (MCI). METHODS: This was a cross-sectional, community-based study. RESULTS: Women with MCI had higher total plasma homocysteine than healthy-comparison subjects. There was also a nonsignificant excess of APOE epsilon4 carriers in the MCI than in the healthy group. Participants with SMC had higher depression and anxiety scores than healthy-comparison subjects, but did not differ from subjects in the healthy-comparison group in relation to their total plasma homocysteine and APOE epsilon4 distribution. CONCLUSIONS: MCI seems to be more closely related to well-established risk factors for dementia than is SMC.     

Cases with mild cognitive impairment and Alzheimer's disease fail to benefit from repeated exposure to episodic memory tests as compared with controls

Memory tests may be predictive for cognitive decline. We investigated the sensitivity and change in performance over time of the Hopkins Verbal Learning Test (HVLT) and the Mini-Mental Status Examination (MMSE) for Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) when compared to cognitively healthy controls.Participants included elderly controls (n = 54), MCI (n = 19) and AD cases (n = 28) from OPTIMA. The MMSE and the HVLT (version 1) were administered twice to all subjects with an interval of 2-3 years.MCI and AD cases had poorer performance than controls on the HVLT and MMSE at both testing episodes (p < 0.05). The HVLT profile over time showed a learning effect in the control group (P < 0.0001), a trend to decline in the AD group (p = 0.09) and no change in the MCI group (P = 0.8). A subgroup of MCI subjects had lower HVLT scores at follow-up. The MMSE profile showed no significant change over time for all three groups (P > 0.05). The HVLT had better sensitivity and specificity compared to the MMSE for detecting MCI and AD.The HVLT is not only valuable for cross-sectional designs but has also proved to be valuable in a longitudinal design. Cognitively healthy controls showed evidence of learning strategies on the HVLT after a 2-3 year interval, with improved scores at the second testing episode. By contrast, an MCI group showed no benefits of previous exposure to this test. Lack of use of learning strategies on the HVLT may be an important marker of the likelihood of cognitive decline to MCI or dementia.     

Cerebral Amyloid Positivity Prediction Models Using Clinical Data in Subjects With Mild Cognitive Impairment and Dementia

ObjectiveDue to high cost of amyloid imaging, its use of amyloid imaging to confirm amyloid pathology is limited in clinical practice. It is of importance to develop a model to predict cerebral amyloid positivity using clinical data obtained from a memory clinic. MethodsA total of 410 participants who had symptom of subjective cognitive decline and underwent amyloid PET and apolipoprotein ε (APOE) genotyping were retrospectively enrolled from January 2016 to January 2019. Models for cerebral amyloid positivity prediction were developed in all subjects, mild cognitive impairment (MCI) subjects, and Alzheimer’s disease (AD) dementia subjects through multivariate logistic regression analysis. The performance of the models was assessed using receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) values. ResultsAge, sex, years of education, body mass index (BMI), APOE4, and mini mental state examination score (MMSE) were selected for the final model for all subjects. The AUC value of the ROC curve was 0.775. Age, sex, years of education, BMI, and APOE4 were selected for the final model for MCI subjects. The AUC value was 0.735. Age, sex, years of education, BMI, APOE4, MMSE, and history of hypertension were selected for the final model for AD dementia subjects. The AUC value was 0.845. ConclusionThis study found that models using clinical data can predict cerebral amyloid positivity according to cognitive status. These models can be useful as a screening tool predict cerebral amyloid deposition in cognitively impaired patients in a memory clinic.     

White-matter vascular lesions correlate with alpha EEG sources in mild cognitive impairment

It is an open issue if vascular and Alzheimer's disease (AD) lesions represent additive factors in the development of mild cognitive impairment (MCI), as a preclinical stage of Alzheimer's disease (AD) at group level. In the present study, we tested the hypothesis that electroencephalographic (EEG) alpha rhythms, which are affected (i.e. decreased in amplitude) by AD processes, are relatively preserved in MCI subjects in whom the cognitive decline is mainly explained by white-matter vascular load. Resting EEG was recorded in 40 healthy elderly (Nold), 80 MCI, and 40 AD subjects. In the MCI subjects, white-matter vascular load was quantified based on MRI (0-30 Wahlund visual rating scale). EEG rhythms of interest were delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), and beta 2 (20-30Hz). Low resolution electromagnetic source tomography (LORETA) was used for EEG source analysis. As expected, we observed that alpha 1 sources in parietal, occipital, and temporal areas were lower in amplitude in the AD and MCI subjects than in the Nold subjects, whereas the amplitude of wide delta sources was higher in the AD than in the Nold and MCI subjects. As novel results, the amplitude of parietal, occipital, and temporal alpha 1 sources was higher in the MCI V+ (high vascular load; N=42; MMSE=26) than MCI V- group (low vascular load; N=37; MMSE=26.7). Furthermore, a weak but significant (p<0.05) positive statistical correlation was found between the parietal alpha 1 sources and the score of Wahlund scale across all MCI subjects (i.e. the more severe white-matter lesions, the higher parietal alpha source power). The present results are in line with the additive model of cognitive impairment postulating that this arises as the sum of neurodegenerative and cerebrovascular lesions.     

Odor Identification and Self-reported Olfactory Functioning in Patients with Subtypes of Mild Cognitive Impairment

Olfactory dysfunction is a very early symptom of Alzheimer's disease (AD), and olfactory dysfunction has also been found in mild cognitive impairment (MCI). The goal of the present study was to compare odor identification ability and self-reported olfactory functioning in patients with different types of MCI. We included 104 elderly participants classified into two groups: patients with mild cognitive impairment (MCI) and elderly controls (EC). Based on their performance in neuropsychological testing the study population was divided into four groups of participants based on cognitive features: amnestic MCI single domain (11), amnestic MCI multiple domain (19), non-amnestic MCI single domain (21) and non-amnestic MCI multiple domain (13), respectively. The MCI patients were compared to 40 elderly controls (EC) controls with no cognitive deficit. Comparison for odor identification revealed a significant difference between amnestic MCI multiple domain patients and the EC group. No other group comparison was significant. Statistical analyses for self-reported olfactory functioning revealed no significant group differences between any subgroup of MCI patients and the control group. Correlational analyses indicated that odor identification ability was related to cognition whereas no relationship was found for self-reported olfactory functioning. The present study showed that amnestic MCI patients with additional deficits in other cognitive domains have a specific odor identification impairment. Together with cognitive testing, olfactory testing may more accurately help predict whether or not a patient with MCI will convert to AD in the near future.     

Assessment of Alzheimer's disease risk with functional magnetic resonance imaging: an arterial spin labeling study

Functional magnetic resonance imaging (fMRI) of older adults at risk for Alzheimer's disease (AD) by virtue of their cognitive (i.e., mild cognitive impairment [MCI]) and/or genetic (i.e., apolipoprotein E [APOE] ε4 allele) status demonstrate divergent brain response patterns during memory encoding across studies. Using arterial spin labeling MRI, we examined the influence of AD risk on resting cerebral blood flow (CBF) as well as the CBF and blood oxygenation level dependent (BOLD) signal response to memory encoding in the medial temporal lobes (MTL) in 45 older adults (29 cognitively normal [14 APOE ε4 carriers and 15 noncarriers]; 16 MCI [8 APOE ε4 carriers, 8 noncarriers]). Risk groups were comparable in terms of mean age, years of education, gender distribution, and vascular risk burden. Individuals at genetic risk for AD by virtue of the APOE ε4 allele demonstrated increased MTL resting state CBF relative to ε4 noncarriers, whereas individuals characterized as MCI showed decreased MTL resting state CBF relative to their cognitively normal peers. For percent change CBF, there was a trend toward a cognitive status by genotype interaction. In the cognitively normal group, there was no difference in percent change CBF based on APOE genotype. In contrast, in the MCI group, APOE ε4 carriers demonstrated significantly greater percent change in CBF relative to ε4 noncarriers. No group differences were found for BOLD response. Findings suggest that abnormal resting state CBF and CBF response to memory encoding may be early indicators of brain dysfunction in individuals at risk for developing AD.     

Medial temporal lobe atrophy and APOE genotype do not predict cognitive improvement upon treatment with rivastigmine in Alzheimer's disease patients

BACKGROUND: Only a subgroup of subjects with probable AD shows cognitive improvement after treatment with cholinesterase inhibitors. OBJECTIVES: To investigate whether atrophy of the medial temporal lobe and the apolipoprotein E (APOE) genotype could predict cognitive improvement in subjects with probable AD treated with rivastigmine. METHODS: 121 subjects with mild to moderate probable AD were treated for 26 weeks with escalating doses of rivastigmine. Outcome measures were change on the MMSE and the ADAS-Cog between baseline and follow-up and treatment response defined as at least 2 points improvement on the MMSE or at least 4 points improvement on the ADAS-Cog. The study was an open-label multi-centre study in The Netherlands. RESULTS: Subjects with medial temporal lobe atrophy (MTLA) tended to show more decline on the MMSE after correction for age, sex, education, baseline cognitive score, and dosage at week 26 compared with subjects without MTLA (p = 0.08). A significant interaction between MTLA and dosage at week 26 existed for change on the MMSE and ADAS-Cog: subjects with MTLA showed more cognitive decline than subjects without MTLA only in the group of patients who received a low dosage at week 26. MTLA was not associated with treatment response. The APOE genotype was not associated with change on the MMSE or ADAS-Cog or with treatment response. CONCLUSIONS: MTLA and the APOE genotype are not clinically useful predictors of cognitive response in subjects with probable AD who are treated with rivastigmine.     

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.