Relationship between blood pressure and Alzheimer's disease in Linxian County,China

To investigate the relationship between hypertension and Alzheimer's disease(AD) and the change of Alzheimer's patients' blood pressure(BP) before and after the onset of AD, we conducted this epidemiological study. Subjects for this study were individuals who participated in a large scale, randomized controlled trial of nutritional intervention from 1984 to 1991. Participants were initially screened for dementia using Chinese Mini-Mental State Examination (CMMS) and Activities of Daily Living (ADL). Positive subjects were subsequently administered a detailed neuropsychological and neurobehavioral examination. The diagnosis of AD was made by a consensus conference of psychiatrists using Diagnostic And Statistical Manual Of Mental Disorders-Fourth Edition(DSM-IV) criteria. 16488 subjects were examined and 301 were diagnosed as AD. We compared the prevalence of AD in different populations that were stratified with 1984's systolic or diastolic blood pressure(those four stratifications being high blood pressure, borderline blood pressure, normal, low blood pressure), and compared the change of blood pressure of 301 AD patients between 1984 and 1999-2000, which is before and after the onset of AD respectively. Multiple Logistic Regression (1:1 nested case-control study) was used to assess if hypertension is an independent risk factor for AD, and Trend test was used to assess the relationship between blood pressure and AD. Here we demonstrate that there was a significant difference in AD prevalence among different populations stratified by systolic or diastolic blood pressure (P < 0.01).The prevalence is highest in hypertension group, and lowest in hypotension group. Multiple Logistic Regression identified high blood pressure as a risk factor for AD (OR = 1.97, 95%CI:1.09-3.54, P = 0.02). Trend test showed that there is a significant dose-response relationship between blood pressure and AD (P < 0.0002). For hypertensive AD patients, there was no significant difference in systolic blood pressure(SBP) before and after the onset of AD, but diastolic blood pressure(DBP) decreased dramatically after the onset of AD (P < 0.01); however, the result also showed that DBP decrease occurred in the non-demented group. Based on this, we think the DBP decrease is not related to AD. We further investigated whether BP values differed crossed-sectionally between the AD-patients and non-demented individuals. We found that regardless of SBP or DBP, the BP values of the AD group were all significantly higher than that of non-demented. In summary, these data suggest there is a strong relationship between hypertension and AD; however, the mechanism remains to be studied.     

Brain Serum Amyloid P Levels are Reduced in Individuals that Lack Dementia While Having Alzheimer’s Disease Neuropathology

The neuropathological signs of Alzheimer’s disease (AD) include beta amyloid plaques and neurofibrillary tangles. There is a significant population of individuals that have these key hallmarks but show no signs of cognitive impairment, termed non-demented with AD neuropathology (NDAN). The protective mechanism allowing these individuals to escape dementia is unknown. Serum amyloid P (SAP) is a serum protein associated with wound repair that is elevated in the brains of Alzheimer’s patients and binds to amyloid plaques. Using immunoblotting and immunohistochemistry, we evaluated SAP levels in postmortem samples of hippocampus and frontal cortex in age-matched controls, AD, and NDAN individuals. AD individuals had significantly increased SAP levels compared to normal controls, while NDAN samples had no significant difference in SAP levels compared to normal controls. Our results suggest that low levels of SAP in plaques marks the brains of individuals that escape dementia despite the presence of beta amyloid plaques and tangles.     

O6-methylguanine-DNA methyltransferase in lymphocytes of the elderly with and without Alzheimer's disease

Deficiency in DNA repair has been linked to aging, mutagenesis, carcinogenesis and several types of primary neuronal degeneration. O6-Methylguanine-DNA methyltransferase is a key enzyme in the repair of DNA alkylation damage that removes a methyl group from the O6 position of methylguanine. This study was carried out to determine whether there were any changes in the activity of this enzyme in lymphocytes of patients with Alzheimer's disease (AD) as compared to lymphocytes of age-matched non-demented elderly. The transferase activity in lymphocytes from 19 elderly patients with AD (mean 87.7 fmole/100 micrograms protein +/- SD 44.7) was not statistically different from that in 19 age/sex-matched controls (mean 91.3 fmole/100 micrograms protein +/- SD 40.0). There was no significant trend with age in transferase activity and the activity levels in the elderly subjects studied were the same as those reported previously for younger individuals by this laboratory. It is concluded that a reduction in O6-methylguanine-DNA methyltransferase activity is unlikely to be involved in the etiology or the pathogenesis of AD.     

Neuropathological findings processed by artificial neural networks (ANNs) can perfectly distinguish Alzheimer's patients from controls in the Nun Study

Background  

Many reports have described that there are fewer differences in AD brain neuropathologic lesions between AD patients and control subjects aged 80 years and older, as compared with the considerable differences between younger persons with AD and controls. In fact some investigators have suggested that since neurofibrillary tangles (NFT) can be identified in the brains of non-demented elderly subjects they should be considered as a consequence of the aging process. At present, there are no universally accepted neuropathological criteria which can mathematically differentiate AD from healthy brain in the oldest old.     

White matter lesions and soluble interleukin-1 receptor type II in CSF from demented and non-demented subjects

White matter lesions (WMLs) in the brain is a common, unspecific finding on magnetic resonance imaging appearing both in the healthy elderly as well as in a number of different diseases including dementia disorders. However, the pathophysiological and clinical significance of WMLs in dementia disorders is still unknown. In this study, we investigated the possibility of their origin being inflammatory by studying the correlation between WMLs and cerebrospinal fluid (CSF) levels of the proinflammatory cytokine soluble interleukin-1 receptor type II (sIL-1RII). The sIL-1RII is a member of the IL-1 family, and has been found to be elevated in CSF from Alzheimer's disease (AD) patients. In the present study, two groups of patients complaining of memory disturbances with little or extensive WMLs respectively, were examined, as well as healthy subjects. In accordance with other reports, WML scores (total, periventricular as well as deep lesions) were positively correlated with age but not mini mental state examination (MMSE) scores, and were significantly higher in patients with a dementia diagnosis as compared to non-demented subjects. There were no differences in sIL-1RII levels in CSF regardless of amount of total, periventricular or deep WMLs, nor were there any differences between demented and non-demented subjects. In conclusion, sIL-1RII levels in CSF are not correlated to magnetic resonance imaging WMLs in patients with dementia disorders or in healthy subjects.     

Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer’s Disease

Alzheimer’s disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-α, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid β (Aβ) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-γ levels after anti-CD3/CD28 and CMV pp65 but not after Aβ stimulation, compared to CMV seropositive ND controls. When analysing IFN-γ response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.     

Cadmium and mercury levels in saudi women and its possible relationship with hypertension

The association between elevated blood pressure and blood cadmium and mercury levels was examined (2001–2002) in 185 Saudi women previously selected for a case-control study of lead and hypertension risk. Blood pressure was measured twice according to the World Health Organization recommendations. Cadmium and mercury were determined with graphite furnace and hydride system-atomic absorption spectrometry, respectively. Mean blood cadmium concentrations were 0.874±0.995 μg/L in hypertensive and 0.785±0.665 μg/L in controls. While blood mercury concentrations for hypertensives and controls were 3.506±3.617 μg/L and 3.687±3.186 μg/L, respectively. Participants were classified according to the median of blood cadmium and mercury levels. After adjustment for potentially confounding variables, the final logistic regression analyses revealed that women with blood cadmium ≥0.627 μg/L were 3.934 times were more likely to be hypertensive than those with blood cadmium levels <0.627 μg/L, although this was marginally significant (p=0.098). This was likely the result of the small number of subjects, resulting in the weak power to detect a strong significant difference between hypertensives and control cases. On the other hand, the final regression model showed no association between hypertension and mercury. However, this finding should not be conclusive because of the inappropriate choice of the biomarker indicator. Nevertheless, our study supports the hypothesis that exposure to cadmium might increase the risk of hypertension.     

Processing of the Platelet Amyloid Precursor Protein in the Mild Cognitive Impairment (MCI)

It has been suggested that mild cognitive impairment (MCI) patients deteriorate faster than the healthy elderly population and have an increased risk of developing dementia. Certain blood molecular biomarkers have been identified as prognostic markers in Alzheimer’s disease (AD). The present study was aimed to assess the status of the platelet amyloid precursor protein (APP) metabolism in MCI and AD subjects and establish to what extent any variation could have a prognostic value suggestive of predictive AD in MCI patients. Thirty-four subjects diagnosed with MCI and 45 subjects with AD were compared to 28 healthy elderly individuals for assessing for protein levels of APP, β-APP cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and a disintegrin and metalloproteinase-10 (ADAM-10) by western blot, and for the enzyme activities of BACE1 and γ-secretase by using specific fluorogenic substrates, in samples of platelets. A similar pattern in the healthy elderly and MCI patients was found for BACE1 and PS1 levels. A reduction of APP levels in MCI and AD patients compared with healthy elderly individuals was found. Augmented levels of ADAM-10 in both MCI and AD were displayed in comparison with age-matched control subjects. The ratio ADAM-10/BACE1 was higher for the MCI group versus AD group. Whereas BACE1 and PS1 levels were only increased in AD regarding to controls, BACE1 and γ-secretase activities augmented significantly in both MCI and AD groups. Finally, differences and similarities between MCI and AD patients were observed in several markers of platelet APP processing. Larger sample sets from diverse populations need to be analyzed to define a signature for the presence of MCI or AD pathology and to early detect AD at the MCI stage.     

High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer's disease

A previously unrecognized large pool of Abeta was discovered in freshly drawn plasma of patients diagnosed with Alzheimer's disease (AD) and non-demented control subjects. This Abeta pool was revealed after acid denaturation and chromatographic separation of plasma proteins followed by Abeta quantitation in the 4.5 kDa fractions by europium immunoassay. The mean values of Abeta42 in the AD and control individuals amounted to 236 ng/ml and 38 ng/ml, respectively. These Abeta values are on the average far higher than previously measured. Surprisingly, the circulating Abeta42 is about 16 times more abundant than Abeta40 in the AD population. Addition of Abeta to freshly drawn plasma demonstrated the rapid disappearance of Abeta epitopes, as detected by immunochemical techniques, suggesting either proteolytic degradation or Abeta sequestration. Incubation of Abeta with purified plasma proteins and lipoproteins rapidly decreases detectable levels of free Abeta suggesting epitope masking as the likely mechanism. The free and protein-bound Abetab in the circulation may represent a potential source for deposition in the cerebrovasculature and brain parenchyma of AD.     

Lipid Peroxidation and Antioxidant Enzyme Activities in Vascular and Alzheimer Dementias

It has been reported that oxidative stress may play a role in the pathogenesis of dementia of the Alzheimer type (AD) and the cerebral ischemia which causes vascular dementia (VD). We measured malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities in blood samples from patients with AD and VD and in healthy non-demented controls (CTR) which similar ages to the patients, in order to evaluate the degree of oxidative stress in patients with AD and VD. A sample of 150 subjects consisting of 50 patients with AD; 50 patients with VD and 50 CTR, aged from 65 to 85 years on, was analyzed. Most of the changes observed were in SOD activity and MDA levels. Catalase activity were least affected. Significant differences were observed in SOD and GR activity between males and females in CRT and in patients with AD, but not in VD. We have found a decrease in antioxidant enzymes activities (SOD, CAT, GPx and GR) in patients with AD and VD and significant differences were observed between CRT and AD patients for ages from 65 to 74, 75 to 84 and from 85 years to 94 years in SOD activity and MDA levels (P < 0.001). MDA levels increase with age in VD, AD and CTR. No significant variation with respect to sex were detected, but significant variations in MDA levels were detected between CRT and patients with VD and AD (P < 0.001). We conclude that oxidative stress plays an important role in the brain damage for both AD and VD, being observed higher levels of oxidative stress for AD that for VD.     

老年痴呆与血浆同型半胱氨酸水平关系的临床研究

目的:探讨血浆同型半胱氨酸(homocysteine,Hcy)水平与老年痴呆的相关性。方法:应用全自动生化分析仪以循环酶法检测90例老年痴呆患者的血浆Hcy浓度,并与30例非痴呆患者作为同龄对照组血浆Hcy浓度进行比较;根据Hachinski缺血指数量表评分将老年痴呆分为阿尔茨海默病(Alzheimer’s disease,AD),混合性痴呆(mixed dementia,MD),血管性痴呆(vascular dementia,VD);根据简易精神状态检查量表(Mini-Mental State Examination,MMSE)评分划分痴呆患者严重程度,分为轻度、中度、重度。结果:AD、MD、VD组血浆Hcy水平均显著高于对照组(P<0.01);不同程度痴呆患者血浆Hcy水平有显著性差异(P<0.05),血浆Hcy浓度越高,认知功能损害的程度越重。结论:高Hcy血症可能是老年期痴呆发病的一个重要危险因素,且认知功能减退的程度与血浆同型半胱氨酸浓度呈正相关。     

Levels of Amyloid Beta-42, Interleukin-6 and Tumor Necrosis Factor-Alpha in Alzheimer’s Disease and Vascular Dementia

Amyloid β42 (Aβ42) and proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD) and vascular dementia (VaD). Our aim was to examine whether the changes in these parameters would be able to discriminate the patients with AD from those with VaD and from healthy individuals. We have analyzed the levels of Aβ42, IL-6 and TNF-α in the serum of newly diagnosed 28 AD patients, 16 VaD patients and 26 healthy non-demented controls. We also investigated whether there is an association between Aβ42, IL-6 and TNF-α levels and mini-mental state examination (MMSE) scores and body mass indexes (BMI) of patients. Our data showed a significant decrease in serum Aβ-42 levels in AD patients compared to VaD patients and controls. Levels of IL-6 and TNF-α were not different between AD patients, VaD patients and controls. We observed a correlation between Aβ-42 levels and MMSE scores and BMI levels in both AD and VaD patients. However, Aβ-42 levels were not correlated with IL-6 and TNF-α levels. Significantly lower levels of Aβ42 found in the serum of AD patients than that of VaD patients and controls suggests that it can be a specific biochemical marker for AD.     

Blood Cadmium Concentrations in Women with Ectopic Pregnancy

The purpose of this study is to investigate the relationship between the blood level of cadmium and the occurrence of ectopic pregnancy. Forty-one (41) case patients with ectopic pregnancy and 41 uncomplicated intrauterine pregnant patients as controls were recruited. The concentrations of cadmium (Cd) were measured from blood samples using atomic absorption spectrometry. The cases and controls were similar in age, body mass index, and smoking habits. The median blood level of Cd was 0.32 μg/l (interquartile range [IQR] 0.00–0.71) in the women with ectopic pregnancies and 0.34 μg/l (IQR 0.09–0.59) in the controls. There was no significant association between blood cadmium levels and ectopic pregnancy.     

Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer's disease

The apoE phenotype of 83 patients with probable Alzheimer's disease (AD) and of 164 non-demented controls was determined by isoelectric focusing and Western blotting. The proportion of the e4 allele was 0.548 in AD and 0.202 in controls (P<0.0001). The effect was seen in both early-onset and late-onset AD patients. The risk of AD in 4 homozygotes was 18-fold greater than in individuals without the 4 allele. ApoE concentrations were measured in serum and cerebrospinal fluid (CSF) from a subgroup of patients with AD (n=72) and controls (n=84) by a sandwich enzyme-linked immunosorbent assay. Although serum apoE concentrations were lower in individuals with the 4 allele than in those without the e4 allele, CSF apoE concentrations did not vary in different phenotype groups. However, CSF apoE levels were lower in AD patients than in controls. We conclude that the inheritance of the 4 allele of apoE is a risk factor for AD in the Finnish population.     

Decreased Proportion of Cytomegalovirus Specific CD8 T-Cells but No Signs of General Immunosenescence in Alzheimer’s Disease

Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naïve T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer’s disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naïve CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.     

The Inflammatory Marker YKL-40 Is Elevated in Cerebrospinal Fluid from Patients with Alzheimer’s but Not Parkinson’s Disease or Dementia with Lewy Bodies

A major difference in the revised diagnostic criteria for Alzheimer’s disease (AD) is the incorporation of biomarkers to support a clinical diagnosis and allow the identification of preclinical AD due to AD neuropathological processes. However, AD-specific fluid biomarkers which specifically distinguish clinical AD dementia from other dementia disorders are still missing. Here we aimed to evaluate the disease-specificity of increased YKL-40 levels in cerebrospinal fluid (CSF) from AD patients with mild to moderate dementia (n = 49) versus Parkinson’s disease (PD) (n = 61) and dementia with Lewy bodies (DLB) patients (n = 36), and non-demented controls (n = 44). Second we aimed to investigate whether altered YKL-40 levels are associated with CSF levels of other inflammation-associated molecules. When correcting for age, AD patients exhibited 21.3%, 27.7% and 38.8% higher YKL-40 levels compared to non-demented controls (p = 0.0283), DLB (p = 0.0027) and PD patients (p<0.0001). The AD-associated increase in YKL-40 was not associated with CSF P-tau, T-tau or Aβ42. No relationship between increased YKL-40 and levels of the astrocytic marker glial-fibrillary acidic protein (GFAP), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein 10 (IP-10) could be identified. Our results confirm previous reports of an age-associated increased in CSF YKL-40 levels and further demonstrate increased CSF YKL-40 in AD patients versus non-demented controls and patients with DLB or PD. The increase in YKL-40 levels in the AD patients was unrelated to the established CSF AD biomarkers and the inflammatory markers GFAP, MCP-1, IP-10 and IL-8, proposing YKL-40 as a marker of yet to be identified AD-related pathological processes.     

Biological monitoring of lead and cadmium in human hair and nail and their correlations with biopsy materials, age and exposure

Hair and fingernails of exposed and unexposed subjects were analyzed for their lead (Pb) and cadmium (Cd) contents by atomic absorption spectrophotometer with graphite furnace and air-acetylene flame. Hair and nail Pb concentrations in occupationally exposed subjects ranged between 1.020-409.726 and 8.130-765.306 microg/g and in environmentally unexposed subjects 0.123-25.160 and 1.076-65.613 microg/g, respectively. Similarly, hair and nail Cd concentrations in occupationally exposed subjects ranged between 0.014-22.086 and 0.214-35.714 microg/g and in environmentally unexposed subjects 0.113-1.627 and 0.028-8.108 microg/g, respectively. A significant correlation was observed between Pb hair and nail concentrations in exposed subjects at P < 0.05, as compared to unexposed subjects and Cd hair and nail in exposed, as well as unexposed subjects. With respect to exposure, levels of Pb in hair and nails were found to be significant in exposed subjects, compared to unexposed ones and levels of Cd were significant only in nails of exposed ones. With respect to age, no significant correlation was found between hair and nail Pb and Cd concentrations in both exposed and unexposed subjects.     

Cigarette smoking during pregnancy: comparison of biomarkers for inclusion in epidemiological studies

Using proteomic approach in cerebrospinal fluid (CSF) we identified pigment epithelium-derived factor (PEDF) and Haptoglobin (Hp) as putative markers that could discriminate between AD and other dementias. ELISA assays were developed to measure the levels of PEDF and Hp in CSF from patients with AD (AD, n?=?27), non-AD (NAD, n?=?30) and in non-demented patients (ND, n?=?27). The combined assessment of PEDF, Hp and Tau levels, using Iterative Marginal Optimization, improved the differential diagnosis of AD, especially in patients with moderate to severe dementia (p<0.002). This pilot study highlights the probable different contribution of oxidative mechanisms in dementia.     

Comparative platelet proteome analysis reveals an increase of monoamine oxidase-B protein expression in Alzheimer's disease but not in non-demented Parkinson's disease patients

Monoamine oxidase-B (Mao-B) catalysing the breakdown of the neurotransmitter dopamine, is known to be involved in the pathophysiology of Parkinson's (PD) and Alzheimer's disease (AD). Increased brain Mao-B activity is associated with AD. This alteration can also be seen in platelets, albeit the cause has hitherto remained elusive. To gain a deeper understanding of the etiology of AD, the platelet proteome was characterised, (2D DIGE pH6-9, including Mao-B) from 150 individuals: 34 AD, 13 vascular dementia, 15 non-demented PD patients, 49 matched controls, 18 oldest old and 21 young individuals. One significant change was noted after applying false discovery rate with the upregulation of the Mao-B expression (30% adjusted P value<0.001; effect size 1.31) in AD compared to age- and sex-matched controls. In contrast, Mao-B levels were unchanged in PD to matched controls. Western blot and mRNA analyses verified these findings. Moreover, Mao-B concentration correlated with age in the cognitive healthy individuals (r=0.53; P<0.001) and PD patients but not in those suffering from AD (r=-0.03; P=0.874). Mao-B activity correlated with the increased Mao-B protein expression in AD (r=0.81; P=0.016). We suggest that Mao-B platelet protein level may serve as a biomarker for age-related dementia, especially AD.