Decreased plasma levels of soluble receptor for advanced glycation end products in mild cognitive impairment

Growing evidence advanced the idea that the soluble form of the receptor for advanced glycation end-products (sRAGE) might serve as a risk marker for several disorders including Alzheimer disease. We found a reduced level of circulating sRAGE in patients with mild cognitive impairment (MCI). The reduction of sRAGE in MCI, as well as the anticipation of the disease in patients with the lowest sRAGE levels (相似文献   

Association between the RAGE G82S polymorphism and Alzheimer’s disease

The receptor for advanced glycation end products (RAGE) is associated with several pathological states including Alzheimer’s disease (AD) pathology, while its soluble form (sRAGE) acts as a decoy receptor. We have tested for association of AD with a functional single-nucleotide polymorphism (SNP) in the RAGE gene (G82S; rs2070600), a SNP associated with increased ligand affinity of RAGE. Analysis of a Chinese cohort (276 cases; 254 controls) showed a higher prevalence of the RAGE 82S allele and GS + SS genotype in the patients [82S vs. 82G: P = 0.017, odds ratio (OR) = 1.431; GS + SS vs. GG: P = 0.025, OR = 1.490]. Further stratification analysis revealed that the association of the RAGE G82S polymorphism with AD was significant in early onset AD stratum. Moreover, plasma sRAGE levels were lower in AD than in normal elderly controls, and the presence of the risk allele was associated with further plasma sRAGE reduction and a fast cognitive deterioration. The present study provides preliminary evidence that the RAGE G82S variant is involved in genetic susceptibility to AD.     

Homocysteine, vitamin B12, and folic acid levels in Alzheimer's disease, mild cognitive impairment, and healthy elderly: baseline characteristics in subjects of the Australian Imaging Biomarker Lifestyle study

There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.     

Early biomarkers for post-stroke cognitive impairment

The aim of this study was to investigate whether some biomarkers could predict cognitive impairment after stroke. One hundred fifty-two first-ever stroke patients were recruited within 6-72?h after the onset of symptoms. Blood was drawn within 1?h after admission for determining biomarkers. Cognitive function was assayed 2?weeks after stroke. The patients were divided into four groups: stroke, vascular cognitive impairment with no dementia (VCIND), vascular dementia (VaD), and mixed dementia (MD). Forty healthy subjects were used as controls. The results indicated that lower soluble receptor levels for advanced glycation end products (sRAGE) and higher β-secretase enzyme (BACE1) and neprilysin (NEP) levels were found in the VCIND, VaD, and MD groups. In addition, the percentages of ε3/ε4 genotypes and ε4 alleles in the VCIND, VaD, and MD groups were higher than in the stroke group. Correlation analysis determined that sRAGE, BACE1, and NEP were significantly related to the results of neuropsychological assessments. Logistic regression analysis, however, suggested that only sRAGE and BACE1 changed ahead of cognitive impairment after stroke. In conclusion, only BACE1 and sRAGE, not NEP or APOE genotypes, may be biomarkers diagnosing post-stroke cognitive impairment.     

Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia

BACKGROUND: The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in vascular disease and neurodegeneration. Low levels of its secreted isoform, soluble RAGE (sRAGE), have been regarded as a putative risk factor for atherosclerosis. In addition, administration of sRAGE has been shown to reduce development of cerebral beta-amyloidosis in an Alzheimer disease mouse model. OBJECTIVE: To investigate the role of sRAGE as a biological marker for Alzheimer disease and vascular dementia. DESIGN: Cross-sectional study of 152 patients with a clinical diagnosis of Alzheimer disease, 91 with vascular dementia and 161 control subjects. MAIN OUTCOME MEASURE: Plasma levels of sRAGE. RESULTS: Levels of sRAGE were significantly reduced in the plasma of patients with Alzheimer disease compared with that for those with either vascular dementia (P<.05) or with controls (P<.001). CONCLUSIONS: Patients with Alzheimer disease have reduced levels of sRAGE in plasma compared with patients with vascular dementia and controls. The striking reduction of circulating sRAGE in Alzheimer disease further supports a role for the RAGE axis in this clinical entity and requires further investigation.     

Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer's disease

Oxidative stress has been shown to be a triggering event in the pathogenesis of Alzheimer's disease (AD). However, little evidence exists on the role of oxidative imbalance in Mild Cognitive Impairment (MCI), a group with a high risk of progression to AD. We therefore assessed the peripheral blood levels of a broad spectrum of non-enzymatic and enzymatic antioxidant defenses, as well as lipid and protein oxidation markers and nitrogen oxidative species in 85 MCI patients, 42 mild AD patients and 37 age-matched controls. In mild AD patients, the plasma levels of vitamin E were significantly decreased, while the plasma concentration of oxidized glutathione was increased in both MCI and mild AD patients. An increase in plasmatic and erythrocytes oxidative markers was also observed in MCI and mild AD patients as compared to controls. In both patients groups, increased levels of plasma antioxidants were found in females, whereas apolipoprotein E epsilon4 allele carriers showed higher indices of intracellular oxidative markers. Moreover, in MCI patients, cognitive function positively correlates with antioxidant levels. This study shows that most of the oxidative changes found in mild AD patients are already present in the MCI group, and that progression to AD might be accompanied by antioxidant depletion.     

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.     

Homocysteine,apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment

BACKGROUND: Alzheimer's disease (AD) is the most common dementia disorder in elderly people. Currently, the only known genetic factor associated with the development of sporadic AD is the apolipoprotein E (ApoE) 4 allele. There is a need to identify other environmental and genetic risk factors that could modulate the risk of developing sporadic AD. OBJECTIVE: To analyse the correlation between the ApoE and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma homocysteine levels and vitamins (B(12) and folic acid) concentrations in serum from patients with AD and mild cognitive impairment (MCI) as compared with control group. METHODS: The study was carried out in 99 AD patients, 98 subjects with MCI and 100 healthy subjects. Diagnosis of probable AD was made according to the NINCDS-ADRDA and DSM-IV criteria. The following factors were analysed: age, gender, duration of disease, concentration of plasma total homocysteine, folic acid and vitamin B(12) in the serum and the polymorphism of MTHRF and ApoE genes. The results obtained were analysed by multivariate analysis of regression. RESULTS: We found that plasma total homocysteine is increased in AD patients (p < 0.0001) and depended on the MTHFR T/T genotype in the presence of low folate levels (p < 0.05). The increased frequency of ApoE4 allele in the AD population was independent of homocysteine, folic acid and vitamin B(12) levels and MTHFR status. CONCLUSIONS: We conclude that the concentration of plasma total homocysteine is increased in AD patients. This may be associated with the T/T genotype in the MTHFR gene; however, the distribution of the MTHRF C677T polymorphism in the Polish population does not differ in AD and controls.     

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.     

高级糖基化终末产物在认知功能障碍发病中的作用

高级糖基化终末产物（AGEs）是由蛋白质非酶促化反应生成的不可逆的终产物，高级糖基化终末产物受体（RAGE）是其体内重要的受体。通过临床、动物实验及病理研究发现，AGEs与认知功功能损害的发生有关，对神经细胞的直接毒性作用、对β-淀粉样蛋白（Ap）、TAU蛋白及a-突触核蛋白（a—Synuclein）等修饰、炎症反应和脑血管损伤是AGEs参与认知损害发生的重要机制。通过药物拮抗AGEs的作用可能是治疗认知障碍的一个有效途径。     

Plasma levels of soluble receptor for advanced glycation end products in Alzheimer's disease

Background: A decreased plasma level of soluble form of the receptor for advanced glycation end products (sRAGE) in patients with Alzheimer's disease (AD) has been reported. However, no evidence has shown whether the sRAGE plasma level of AD patients may differentiate from other types of dementia. Methods: Our study assessed sRAGE concentrations in the following 121 individuals in Chongqing area: 36 patients with AD, 12 with vascular dementia (VaD), 14 with mixed dementia (MD), 24 with other dementia (OD) including Parkinson's disease dementia, frontotemporal dementia, paralytic dementia and 35 cognitively normal controls. The total plasma level of sRAGE was determined using sandwich ELISA method. Results: sRAGE concentration in AD is significantly decreased compared with healthy controls. However, the receiver operating characteristic curve analysis of sRAGE between the AD and the control shows a low diagnostic accuracy. Conclusions: Our results demonstrate that sRAGE may assist the diagnosis of AD from normal individuals, but cannot differentiate AD from VaD, MD or OD.     

Abnormal visual search in mild cognitive impairment and Alzheimer's disease

Our aim was to further characterize the clinical concept of mild cognitive impairment (MCI). We examined the status of visual attention-related processing in such patients in relation to healthy older adults and patients with Alzheimer's disease (AD) by measuring performance on a computer-based visual search task. We tested 20 older adult control participants, 13 patients with amnestic mild cognitive impairment and 12 patients with AD. Patients with AD and with MCI exhibited a significant detriment in visual search performance compared to the older adult controls. The deficit in visual search was greater for the patients with AD than the patients with MCI. The pattern of results displayed by the MCI group indicates that patients who appear clinically to suffer only from a deficit in memory also display a deficit in visual attention-related processing, which although not as severe as those with AD, represents a significant detriment in such performance compared to that seen in healthy ageing.     

Soluble receptor for advanced glycation end products in multiple sclerosis: a potential marker of disease severity

OBJECTIVES: To compare serum levels of the receptor for advanced glycation end products (sRAGE) between multiple sclerosis (MS) patients and healthy control subjects, and to investigate whether serum sRAGE levels correlate with MS disease severity as indicated by the Kurtzke Expanded Disability Status Scale (EDSS). METHOD: 37 patients with clinical diagnosis of MS and 22 healthy control subjects were investigated in a cross-sectional study using enzyme-linked immunosorbent assays (ELISA). RESULTS: Serum levels of sRAGE were found to be significantly lower in MS patients compared to levels in healthy controls (p = 0.005). A trend toward lower levels of serum sRAGE was observed in female MS patients compared to their male counterparts (p = 0.05). A relationship between sRAGE and EDSS, and sRAGE and rate of clinical relapse was observed (p = 0.012). CONCLUSION: The significant reduction of sRAGE in MS patients relative to healthy controls supports the potential role for RAGE axis in MS clinical pathology. Lower levels of sRAGE may be associated with enhanced inflammatory responses. Based on these observations, further investigations into the role of sRAGE in MS clinical pathology is warranted.     

Impact of cognitive impairment on mild dementia patients and mild cognitive impairment patients and their informants

BACKGROUND: The aim of this study was to identify key aspects of the impact of cognitive impairment on patients with mild cognitive impairment (MCI) and mild probable Alzheimer disease (AD) and their informants, and identify overlap and differences between the groups. METHODS: Structured focus group discussions were conducted with MCI patients, AD patients, MCI informants, and AD informants. Participants were recruited from memory clinics in the U.K. and the U.S.A. A total of 20 AD and 20 MCI patients and 16 AD and 11 MCI informants participated. Sessions were content reviewed to identify key impacts of cognitive impairment; results were compared across diagnostic groups and for patients and informants. RESULTS: Seven key themes emerged: uncertainty of diagnosis, skill loss, change in social and family roles, embarrassment and shame, emotionality, insight, and burden. Patients were able to discuss the impact of cognitive impairment on their lives and reported frustration with recognized memory problems, diminished self-confidence, fear of embarrassment, concerns about changing family roles due to cognitive impairment, and anxiety. Informants reported more symptoms and more impairment than did patients and indicated increased dependence on others among patients. CONCLUSION: MCI and mild AD exert substantial burden on patients' lives and the lives of those close to them.     

Multiple cognitive deficits in amnestic mild cognitive impairment

OBJECTIVE: To determine if more widespread cognitive deficits are present in a narrowly defined group of patients with the amnestic form of mild cognitive impairment (MCI). METHODS: From a larger sample of patients clinically diagnosed as meeting the criteria of Petersen et al. for amnestic MCI, we selected 22 subjects who had Clinical Dementia Rating scores of zero on all domains besides memory and orientation. These MCI subjects with presumably isolated memory impairments were compared to 35 age-matched normal controls and 33 very mild Alzheimer's disease (AD) patients on a battery of neuropsychological tests. RESULT: In addition to the expected deficits in episodic memory, the amnestic MCI group performed less well than the controls but better than the AD group on design fluency, category fluency, a set shifting task and the Stroop interference condition. Over half the amnestic MCI group (vs. none of the normal controls) scored at least 1 standard deviation below control means on 4 or more of the nonmemory cognitive tasks. CONCLUSIONS: Isolated memory impairment may be fairly uncommon in clinically diagnosed amnestic MCI patients, even when the criteria for amnestic MCI are fairly narrow. Additional cognitive impairments are likely to include fluency and executive functioning. These more diffuse deficits argue for comprehensive cognitive assessments, even when the patient and family are reporting only memory decline, and are consistent with the increase in attention paid to the heterogeneity of MCI.     

Everyday memory impairment of patients with mild cognitive impairment

We evaluated everyday memory impairment in 24 patients with mild cognitive impairment (MCI) with the Rivermead Behavioral Memory Test (RBMT) and compared the scores with those of 48 age-, sex- and education-matched normal controls (NC) and 48 age-, sex- and education-matched Alzheimer disease (AD) patients. Overall everyday memory was impaired in MCI patients but the severity was milder than that in AD patients. The MCI patients showed impairment of everyday memory tasks requiring delayed recall. But they could normally perform tasks immediately after memorizing, except for recalling and retracing a simple new route. The total Profile score correctly classified 100% of the MCI patients and 91.7% of NC, thus demonstrating the usefulness of the RBMT for diagnosing MCI patients. Prospective memory tasks were not useful for detecting the patients with MCI.     

Plasma biomarkers for mild cognitive impairment and Alzheimer's disease

Purpose of review: With the move toward development of disease modifying treatments, there is a need for more specific diagnosis of early Alzheimer's disease (AD) and mild cognitive impairment (MCI), plasma biomarkers are likely to play an important role in this. We review the current state of knowledge on plasma biomarkers for MCI and AD, including unbiased proteomics and very recent longitudinal studies.Recent findings: With the use of proteomics methodologies, some proteins have been identified as potential biomarkers in plasma and serum of AD patients, including alpha-1-antitrypsin, complement factor H, alpha-2-macroglobulin, apolipoprotein J, apolipoprotein A-I. The findings of cross-sectional studies of plasma amyloid beta (Aβ) levels are conflicting, but some recent longitudinal studies have shown that low plasma Aβ1–42 or Aβ1–40 levels, or Aβ1–42/Aβ1–40 ratio may be markers of cognitive decline. Other potential biomarkers for MCI and AD reflecting a variety of pathophysiological processes have been assessed, including isoprostanes and homocysteine (oxidative stress), total cholesterol and ApoE4 allele (lipoprotein metabolism), and cytokines and acute phase proteins (inflammation). A panel of 18 signal proteins was reported as markers of MCI and AD.Summary: A variety of potential plasma biomarkers for AD and MCI have been identified, however the findings need replication in longitudinal studies. This area of research promises to yield interesting results in the near future.     

Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment

Cellular mechanisms conferring neuroprotection in the brains of patients with Alzheimer disease (AD) remain incompletely understood. Erythropoietin (Epo) and the erythropoietin receptor (EpoR) are expressed in neural tissues and protect against oxidative and other stressors in various models of brain injury and disease. Our objective in this study was to determine whether EpoR is upregulated in the brains of persons with sporadic AD and mild cognitive impairment (MCI). Postmortem hippocampus and temporal cortex from subjects with AD, MCI, and no cognitive impairment (NCI) were procured from the Religious Orders Study. Total immunoreactive EpoR protein was determined by Western blotting. Astrocytes expressing immunoreactive EpoR were quantified in 4 temporal and 6 hippocampal regions, and correlated with clinical, neuropsychologic, and neuropathologic indices. Total immunoreactive EpoR protein was markedly increased in AD and MCI temporal cortex versus NCI tissues. Composite measures of glial EpoR expression in temporal cortex layers I to IV were significantly greater in the MCI group compared with the NCI and AD groups. Hippocampal EpoR scores were increased in persons with MCI and AD relative to those with NCI. There was substantial subregional heterogeneity in disease-related EpoR expression patterns in AD and MCI temporal cortex and hippocampus. There was no association of EpoR-positive astrocytes with summary measures of global cognition or AD pathology. We conclude that upregulation of EpoR in temporal cortical and hippocampal astrocytes is an early, potentially neuroprotective, event in the pathogenesis of sporadic AD.     

Oxidative damage and progression to Alzheimer's disease in patients with mild cognitive impairment

Recent studies show that most of the oxidative changes found in Alzheimer's disease (AD) are already present in mild cognitive impairment (MCI) patients. The question arises as to whether oxidative stress has a role in the progression of MCI to AD. We conducted a longitudinal study on 70 MCI patients, and the peripheral blood levels of a broad spectrum of non-enzymatic and enzymatic antioxidant defenses, as well as lipid and protein oxidation markers and nitrogen oxidative species were determined. At baseline, there were no differences in any of the indexes of oxidative damage between stable MCI patients (MCI-MCI) and patients that progressed to AD (MCI-AD). Cellular levels of lipid peroxidation markers increased in both groups and this was accompained in MCI-AD, but not in MCI-MCI patients, by a significant decrease in cellular antioxidant defenses (oxidyzed/reduced glutathione ratio and vitamin E). Among MCI-AD patients, the longitudinal decrease in cellular vitamin E was associated with the deterioration in cognitive performance. These results suggest that accumulation of oxidative damage may start in pre-symptomatic phases of AD pathology and that progression to AD might be related to depletion of antioxidant defenses.