Deficits of spatial and task-related attentional selection in mild cognitive impairment and Alzheimer's disease

Visual selective attention was assessed with a partial-report task in patients with probable Alzheimer's disease (AD), amnestic mild cognitive impairment (MCI), and healthy elderly controls. Based on Bundesen's “theory of visual attention” (TVA), two parameters were derived: top-down control of attentional selection, representing task-related attentional weighting for prioritizing relevant visual objects, and spatial distribution of attentional weights across the left and the right hemifield.Compared with controls, MCI patients showed significantly reduced top-down controlled selection, which was further deteriorated in AD subjects. Moreover, attentional weighting was significantly unbalanced across hemifields in MCI and tended to be more lateralized in AD. Across MCI and AD patients, carriers of the apolipoprotein E ε4 allele (ApoE4) displayed a leftward spatial bias, which was the more pronounced the younger the ApoE4-positive patients and the earlier disease onset.These results indicate that impaired top-down control may be linked to early dysfunction of fronto-parietal networks. An early temporo-parietal interhemispheric asymmetry might cause a pathological spatial bias which is associated with ApoE4 genotype and may therefore function as early cognitive marker of upcoming AD.     

Prediction of Alzheimer's disease in mild cognitive impairment: a prospective study in Taiwan

The relationship between apolipoprotein E (ApoE) and clinical manifestations of mild cognitive impairment (MCI) has not been investigated in non-Caucasian populations. This prospective study was conducted in an ethnic Chinese population to evaluate the correlations of ApoE genotype, cognitive performance, medial temporal structure volumes, and clinical outcome in amnestic MCI. Twenty normal elders, 58 MCI, and 20 mild Alzheimer's disease (AD) patients received neuropsychological, MRI, and ApoE genotype assessments at baseline. Patients with MCI had intermediate cognitive performance and hippocampal volumes between those in normal and AD groups. In each diagnostic group, 4 carriers (E4+) consistently had smaller hippocampal volume than non-carriers (E4−) did. Nineteen MCI subjects (32.7%) converted to AD during the 3-year study period. Compared with MCI non-converters and E4− MCI converters, E4+ MCI converters had the smallest hippocampal volume. However, 4 was not a predictor for AD. Both cognitive performance and hippocampal volume were predictive for progression to AD. However, stepwise Cox regression model integrating both neuropsychological and radiological variables showed that global cognitive performance was the only significant predictor for AD. A poor global cognitive score may be more crucial than a small hippocampal volume in the prediction of AD.     

ApoE genotype and abnormal auditory cortical potentials in healthy older females

Apolipoprotein E (ApoE) status and gender are risk factors for the development of Alzheimer's disease. Alzheimer's disease is more prevalent in female relative to male carriers of the ApoE epsilon 4 gene. We examined cortical sensory (P50, N100) and cognitive (P300) potentials in an auditory target detection task in females as a function of ApoE genotype (ApoE epsilon 4 carriers, ApoE epsilon 4 non-carriers) to define the incidence of abnormalities prior to the clinical expression of cognitive impairments. Both neuropsychological test scores and sensory cortical potentials did not differ between the two ApoE groups. In contrast, cognitive P300 potentials were significantly decreased in amplitude and delayed in latency for ApoE epsilon 4 carriers compared to non-carriers. Four out of the 10 ApoE epsilon 4 carriers had abnormally (>2S.D.) delayed P300 latency compared to one out of 20 non-carriers. Abnormal cognitive processes reflected by P300 latency delays are expressed at significantly higher incidence in normal older females who are carriers of the epsilon 4 allele than in non-carriers of this allele.     

EEG alterations in non-demented individuals related to apolipoprotein E genotype and to risk of Alzheimer disease

Identification of preclinical markers is required for early diagnosis of Alzheimer's disease (AD) and cognitive dysfunction in advancing age. Quantitative EEG was examined in 145 individuals with AD, their unaffected relatives and unrelated individuals. The AD patients and their relatives were stratified by ApoE genotype. The resting EEG parameters were severely changed in AD patients, and in patients carrying the ApoE 4 allele the decrease in alpha power was higher than in 4 non-carriers. The resting EEG parameters were indistinguishable in AD relatives with different ApoE genotypes and similar to EEG pattern in common population. Under hyperventilation the presence of the 4 allele in AD relatives was associated with the manifestation of synchronous high-voltage delta-, theta-activity and sharp-waves, pronounced decrease in alpha and increase in delta and theta relative powers. The data suggest that neurophysiological endophenotype of non-demented individuals at genetic risk for AD, characterized by increased excitability and dysfunction of deep brain and alpha rhythm-generating structures, may be revealed decades before the first clinical symptoms of presumable dementia.     

The Effect of Age Correction on Multivariate Classification in Alzheimer’s Disease,with a Focus on the Characteristics of Incorrectly and Correctly Classified Subjects

The similarity of atrophy patterns in Alzheimer’s disease (AD) and in normal aging suggests age as a confounding factor in multivariate models that use structural magnetic resonance imaging (MRI) data. To study the effect and compare different age correction approaches on AD diagnosis and prediction of mild cognitive impairment (MCI) progression as well as investigate the characteristics of correctly and incorrectly classified subjects. Data from two multi-center cohorts were included in the study [AD = 297, MCI = 445, controls (CTL) = 340]. 34 cortical thickness and 21 subcortical volumetric measures were extracted from MRI. The age correction approaches involved: using age as a covariate to MRI-derived measures and linear detrending of age-related changes based on CTL measures. Orthogonal projections to latent structures was used to discriminate between AD and CTL subjects, and to predict MCI progression to AD, up to 36-months follow-up. Both age correction approaches improved models’ quality in terms of goodness of fit and goodness of prediction, as well as classification and prediction accuracies. The observed age associations in classification and prediction results were effectively eliminated after age correction. A detailed analysis of correctly and incorrectly classified subjects highlighted age associations in other factors: ApoE genotype, global cognitive impairment and gender. The two methods for age correction gave similar results and show that age can partially masks the influence of other aspects such as cognitive impairment, ApoE-e4 genotype and gender. Age-related brain atrophy may have a more important association with these factors than previously believed.     

Potentiation of mitogenesis in adult rat chromaffin cell cultures by immunosuppressive agent FK506

Mild cognitive impairment (MCI) is a transitional state between normal aging and Alzheimer's disease (AD) and is a high-risk condition for dementia. The endothelial nitric oxide synthase (NOS3) gene encodes endothelial NOS, an enzyme that regulates the production of the vasodilatory nitric oxide associated with the cerebral small vessel pathology observed in early AD. We studied the distribution of genotype and allele frequencies of the NOS3 Glu/Asp polymorphism in a sample of 62 MCI subjects and 136 controls. Though no association between NOS3 gene variation and MCI status was observed, MCI cases carrying the Asp variant (T+) performed worse in the Mini-Mental State Examination, Wechsler Memory Scale (Revised) long-term visual memory and the phonetic verbal fluency tests. These results suggest that the T allele is a genetic risk factor for cognitive impairment in the elderly.     

Association between apolipoprotein E genotype,chronic liver disease,and hepatitis B virus

Background/Aims

Apolipoprotein E (ApoE) plays an important role in regulating lipid and lipoprotein metabolism, and ApoE genotypes are known to affect plasma lipoprotein concentrations. We investigated whether ApoE genotype determines the disease outcome in hepatitis B virus (HBV)-infected individuals, and verified the association between ApoE genotype and the occurrence of hepatocellular carcinoma (HCC) in patients with chronic liver diseases of various etiologies.

Methods

This hospital-based, case-controlled study enrolled 156 subjects (47 healthy controls, 50 HBV-related liver cirrhosis patients, and 59 HCC patients). ApoE genotypes were determined using PCR-based ApoE genotyping kits. The biological significance of ApoE genotype was verified by measuring serum ApoE levels using an ELISA kits.

Results

The ε3 allele was the most common allele, with allele frequencies among the entire cohort of 5.8%, 84.3%, and 9.9% for the ε2, ε3, and ε4 alleles, respectively. Significantly more of those patients carrying the ε3/3 genotype had developed liver cirrhosis compared to the control subjects. Being an ApoE4 carrier was associated with a lower probability of developing liver cirrhosis. The allele frequencies and genotype distribution of ApoE did not differ significantly between the liver cirrhosis and HCC patients. The serum level of ApoE was significantly higher in patients with liver cirrhosis than in the healthy controls, but did not differ significantly with the ApoE genotype.

Conclusions

The ApoE ε3/3 genotype frequency was higher in patients with HBV-associated liver cirrhosis than in the controls.     

Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.     

Apolipoprotein E genotype in Spanish schizophrenic patients

Apolipoprotein E (ApoE) is a lipoprotein that, in the central nervous system, is thought to play a role in neuronal growth and repair. ApoE has three isoforms (ApoE2, ApoE3 and ApoE4) coded by three different alleles (epsilon2, epsilon3 and epsilon4). Evidence from family, twin and adoption studies suggest that there is an important genetic contribution to the etiology of schizophrenia. Schizophrenia is in some cases associated with cognitive impairment similar to that of Alzheimer patients; therefore, one may postulate that the ApoE gene, whose role in the dementia of Alzheimer's type has been clearly demonstrated, may also be involved in schizophrenia. In the present study, we have genotyped 114 schizophrenic Spanish patients and 94 healthy matched controls, and found no association between the ApoE genotype and schizophrenia. Subdivision of patients in clinical subgroups showed a slight increase of ApoE4 in early-age onset of the disease and a slight decrease in positive family history for psychiatric diseases; the group with a poor response to neuroleptic drugs had a lower ApoE2 allele frequency. However, as the differences did not reach statistical significance, we cannot draw evidence of an association. Our negative data do not support an involvement of ApoE in schizophrenia, and suggest that the underlying mechanism for the cognitive impairment found in schizophrenic patients is not related to that of Alzheimer's patients nor to a higher prevalence of the ApoE allele 4.     

ApoE基因多态型与维吾尔族高血压患者的关系

目的：研究载脂蛋白E(ApoE)基因多态型与维吾尔族高血压患者的关系。方法：以载脂蛋白E(ApoE)为候选基因，运用聚合酶链式反应—限制性片段长度多态型(PCR—RFLP)方法检测了70例高血压患者及59例正常对照者的ApoE基因型。结果：载脂蛋白E(ApoE)基因的基因型分布在正常组和高血压患者中有极显著差异(P值与对照比较，P＜O．01)。高血压患者组与正常组比较ApoE基因的等位基因的分布也有极显著差异(两组P＝O．0049，P＜O．01)。维吾尔族高血压患者携带的ε4等位基因的发生率明显较携带其他等位基因患者为高。结论：ε4等位基因可能是维吾尔族高血压患者的一个危险因子。     

Effects of ApoE4 and maternal history of dementia on hippocampal atrophy

We applied an automated hippocampal segmentation technique based on adaptive boosting (AdaBoost) to the 1.5 T magnetic resonance imaging (MRI) baseline and 1-year follow-up data of 243 subjects with mild cognitive impairment (MCI), 96 with Alzheimer's disease (AD), and 145 normal controls (NC) scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). MCI subjects with positive maternal history of dementia had smaller hippocampal volumes at baseline and at follow-up, and greater 12-month atrophy rates than subjects with negative maternal history. Three-dimensional maps and volumetric multiple regression analyses demonstrated a significant effect of positive maternal history of dementia on hippocampal atrophy in MCI and AD after controlling for age, ApoE4 genotype, and paternal history of dementia, respectively. ApoE4 showed an independent effect on hippocampal atrophy in MCI and AD and in the pooled sample.     

+10 T/C polymorphisms in the gene of transforming growth factor-beta1 are associated with neurodegeneration and its clinical evolution

Transforming growth factor-beta1 (TGF-beta1) acts as an immunosuppressant by inhibiting the expression of several pro-inflammatory cytokines. Its gene contains single nucleotide polymorphisms (SNPs) at codon +10 (T-->C) and +25 (G-->C) that appear to influence the level of expression of TGF-beta1. We investigated these SNPs in 198 healthy controls (HC), 193 patients with Alzheimer's disease (AD) and 48 patients with mild cognitive impairment (MCI). Among the latter, after a 4-year follow-up, 21 were diagnosed as AD (MCI-->AD) while 18 did not progress (stable MCI). We observed that both the +10 C allele and the CC genotype were over-represented in AD when compared to HC. These variants significantly raised the risk of disease independently of the status of apolipoprotein E4. The CC genotype was also over-expressed in MCI, especially in MCI-->AD. These results suggest that TGF-beta1 may be one of the early markers involved in the inflammatory mechanisms underlying the pathogenesis of AD.     

The Influence of Apolipoprotein E Epsilon4 Polymorphism on qEEG Profiles in Healthy Young Females: A Resting EEG Study

The epsilon4 allele of the Apolipoprotein E (ApoE) gene has been linked to various neurological conditions and the aging process in the elderly. However, evidence has suggested that the influence of ApoE epsilon4 may commence in early life. This study examined the modulatory effects of ApoE epsilon4 on regional neural activity as well as inter-regional neural interactions in a young population aged 19-21. Blood samples and resting state eyes-closed EEG signals were collected from 265 healthy females, and stratified into two groups: epsilon4 carriers and non-carriers. The values of the log-transformed mean power of 18 electrodes and the mutual information of 20 channel pairs across delta, theta, alpha and beta frequencies were analyzed. Our connectivity analysis was based on information theory, which combined Morlet wavelet transform and mutual information calculation. Between-group statistics were performed by independent t-test. We notice a consistent trend across the brain, in which ApoE epsilon4 carriers possess lower regional power at the alpha band. The epsilon4 allele is also associated with lower regional power at the theta frequency in the left frontal and posterior brain regions. Functional connectivity analyses reveal a right-lateralized network that differentiates epsilon4 carriers and non-carriers, with lower connectivity strengths for the former. Our tonic EEG analyses complement those of previous reports in that the ApoE epsilon4 allele has a negative impact on regional neural synchronization and inter-regional neural interaction.     

Brain-derived neurotrophic factor, apolipoprotein E genetic variants and cognitive performance in Alzheimer's disease

Since greater attention has been paid to the direct link of genetic variation to cognition and memory performance, apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) have been the two most frequently studied genes. To investigate the effect of BDNF and ApoE polymorphisms on the cognitive profile of mild-moderate Alzheimer's disease (AD) cases, AD patients, genotyped for ApoE and BDNF polymorphisms, underwent extensive neuropsychological investigation. The effect of either ApoE epsilon4 allele and BDNF genetic variant on the neuropsychological pattern of mental impairment was examined both in terms of group differences in performance on the neuropsychological tests between carriers and non-carriers of each variant and by selecting the best predictor of cognitive performance among demographic and genetic factors by means of a multiple regression analysis. Our data confirm a specific effect caused by the presence and amount of ApoE epsilon4 allele, while they suggest that BDNF genetic variants are not a susceptibility factor to AD.     

Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer's disease

Weight changes are common in aging and Alzheimer's disease (AD) and postmortem findings suggest a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF)-based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Aβ(1-42)), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF-). Results showed that BMI was significantly lower in the CSF+ when compared with the CSF- group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or apolipoprotein E (ApoE) genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and nondemented elderly subjects.     

Implicit spatial contextual learning in healthy aging

Three experiments investigated the aging of implicit spatial and spatiotemporal context learning in 2 tasks. In contextual cuing, people learn to use repeated spatial configurations to facilitate search for a target, whereas in higher order serial learning, they learn to use subtle sequence regularities to respond more quickly and accurately to a series of events. Results reveal a dissociation; overall contextual cuing is spared in healthy aging, whereas higher order sequence learning is impaired in the same individuals. This finding suggests that these 2 forms of implicit learning rely on different neural substrates that age differently; the results are also consistent with recent evidence that fronto-striatal circuits are particularly susceptible to decline in health aging.     

Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease

Objectives

Investigate apolipoprotein E ε4 (APOE4) gene and aging effects on florbetapir F18 positron emission tomography (PET) in normal aging and Alzheimer's disease (AD). Methods: Florbetapir F18 PET images were analyzed from 245 participants, 18–92 years of age, from Avid Radiopharmaceutical's multicenter registered trials, including 86 younger healthy control volunteers (yHC), 61 older healthy control volunteers (oHC), 53 mild cognitive impairment (MCI) patients, and 45 AD dementia patients (DAT). Mean florbetapir standard uptake value ratios (SUVRs) were used to evaluate the effects of APOE4 carrier status, older age, and their interaction in each of these groups. Results: In comparison with non-carriers, the APOE4 carriers in each of the oHC, MCI, and DAT groups had higher mean cortical-to-cerebellar florbetapir SUVRs, patterns of florbetapir PET elevations characteristic of DAT, and a higher proportion meeting florbetapir PET positivity criteria. Only the oHC group had a significant association between mean cortical florbetapir SUVRs and age. In cognitively normal adults, without regards to APOE4 genotype, amyloid began to increase at age 58 (95% confidence interval [CI]: 52.3–63.7), with a predicted typical age of florbetapir positivity occurring around age 71 years. Presence of the APOE4 gene reduced the age of predicted florbetapir positivity in normal aging to around age 56 years, approximately 20 years younger than non-carriers. Interpretation: Cerebral amyloid deposition is associated with APOE4 carrier status in older healthy control subjects and symptomatic AD patients, and increases with age in older cognitively normal individuals. Amyloid imaging positivity appears to begin near age 56 years in cognitively intact APOE4 carriers and age 76 years in APOE4 non-carriers.     

The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men

Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.     

Amyloid‐Aβ Peptide in Olfactory Mucosa and Mesenchymal Stromal Cells of Mild Cognitive Impairment and Alzheimer's Disease Patients

Patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) might develop olfactory dysfunction that correlates with progression of disease. Alteration of olfactory neuroepithelium associated with MCI may be useful as predictor of cognitive decline. Biomarkers with higher sensitivity and specificity would allow to understand the biological progression of the pathology in association with the clinical course of the disease. In this study, magnetic resonance images, apolipoprotein E (ApoE) load, Olfactory Connecticut test and Montreal Cognitive Assessment (MoCA) indices were obtained from noncognitive impaired (NCI), MCI and AD patients. We established a culture of patient‐derived olfactory stromal cells from biopsies of olfactory mucosa (OM) to test whether biological properties of mesenchymal stromal cells (MSC) are concurrent with MCI and AD psychophysical pathology. We determined the expression of amyloid Aβ peptides in the neuroepithelium of tissue sections from MCI and AD, as well as in cultured cells of OM. Reduced migration and proliferation of stromal (CD90⁺) cells in MCI and AD with respect to NCI patients was determined. A higher proportion of anosmic MCI and AD cases were concurrent with the ApoE ε4 allele. In summary, dysmetabolism of amyloid was concurrent with migration and proliferation impairment of patient‐derived stem cells.     

Abnormal event-related potentials in young and middle-aged adults with the ApoE ε4 allele

The largest genetic susceptibility factor for Alzheimer's disease is the Apolipoprotein E (ApoE) ε4 allele. Cognitive decline and olfactory impairment are greater in those positive for the ε4 allele. This study sought to determine if the olfactory event-related potential (OERP), compared to the visual ERP, would be sensitive to these subtle declines. Participants included 40 individuals from two age groups, half of each group were ε4 allele positive and half were ε4 negative. Visual ERPs did not demonstrate significant differences between ApoE groups. OERPs demonstrated robust age by ApoE interactions. P3 latencies were significantly longer in ε4 young and middle age participants. These findings suggest that very early olfactory and cognitive changes related to ApoE status are detectible via the OERP.