Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: implications for Alzheimer's disease

The beginnings of late onset Alzheimer's disease (LOAD) are still unknown; however, the progressive and latent nature of neurodegeneration suggests that the triggering event occurs earlier in life. Aging primates exposed to lead (Pb) as infants exhibited an overexpression of the amyloid-β protein precursor (AβPP), amyloid-β (Aβ) and enhanced pathologic neurodegeneration. In this study, we measured the latent expression of a wide array of brain-specific genes and explored whether epigenetic pathways mediated such latent molecular and pathological changes. We analyzed the levels of proteins associated with DNA methylation, i.e., DNA methyltransferase 1 (Dnmt1), DNA methyltransferase3a (Dnmt3a), methyl-CpG binding protein-2 (MeCP2) and those involved in histone modifications (acetylated and methylated histones). We monitored the expression profiles of these intermediates across the lifespan and analyzed their levels in 23-year-old primate brains exposed to Pb as infants. Developmental Pb exposure altered the gene expression of the arrayed genes, which were predominately repressed, with fewer upregulated genes. The latent induction and repression of genes was accompanied by a significant decrease in the protein levels of Dnmts, MeCP2, and proteins involved in histone modifications. The attenuation of DNA methylation enzymes is consistent with hypomethylating effects, which promote upregulation of the genes, while the alterations in the histone modifiers are associated with the repression of genes. Hence, we deduce that early life exposure to Pb can reprogram gene expression resulting in both upregulation and down-regulation of genes through alternate epigenetic pathways contributing to an enhancement in neurodegeneration in old age.     

Biofunctionalized magnetic nanoparticles for specifically detecting biomarkers of Alzheimer's disease in vitro

Magnetic nanoparticles biofunctionalized with antibodies against β-amyloid-40 (Aβ-40) and Aβ-42, which are promising biomarkers related to Alzheimer's disease (AD), were synthesized. We characterized the size distribution, saturated magnetizations, and stability of the magnetic nanoparticles conjugated with anti-Aβ antibody. In combination with immunomagnetic reduction technology, it is demonstrated such biofunctionalized magnetic nanoparticles are able to label Aβs specifically. The ultralow-detection limits of assaying Aβs in vitro using the magnetic nanoparticles via immunomagnetic reduction are determined to a concentration of ～10 ppt (10 pg/mL). Further, immunomagnetic reduction signals of Aβ-40 and Aβ-42 in human plasma from normal samples and AD patients were analyzed, and the results showed a significant difference between these two groups. These results show the feasibility of using magnetic nanoparticles with Aβs as reagents for assaying low-concentration Aβs through immunomagnetic reduction, and also provide a promising new method for early diagnosis of Alzheimer's disease from human blood plasma.     

Potential inflammatory biomarkers in Alzheimer's disease

The role of the brain's innate immune system in Alzheimer pathogenesis is now well established. Proinflammatory cytokines elaborated by this system, in particular activated microglia-derived interleukin-1 (IL-1), drive a cascade of neurotoxic changes that are important for the development and progression of both the neuritic plaques and neurofibrillary tangles characteristic of Alzheimer's disease. Cytokine expression may also be modulated by variants of genes. For instance, inheritance of certain IL-1 gene variants is associated with Alzheimer's disease. The potential for using blood levels of proinflammatory cytokines as biomarkers of disease progression, however, remains unrealized. The interpretation of cytokine levels in the blood is complicated by the fact, for example, that the overexpression of IL-1 in Alzheimer brain may act to increase adrenal cortisol production through the hypothalamic-pituitary-adrenal axis, which acts to limit macrophage activation and peripheral cytokine production.     

Inflammatory biomarkers in Alzheimer's disease plasma

IntroductionPlasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a “Holy Grail” of AD research and intensively sought; however, there are no well-established plasma markers.MethodsA hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.ResultsTen analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).DiscussionPlasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.     

Plasma biomarkers of Alzheimer's disease

PURPOSE OF REVIEW: The importance of biomarkers of Alzheimer's disease is increasing. The present review aims to offer a general view of plasma biomarkers of Alzheimer's disease and to discuss their relevance and limitations. RECENT FINDINGS: The broad overlap in the plasma amyloid beta protein (Abeta) levels between patients with Alzheimer's disease and control individuals indicates that the plasma Abeta level cannot differentiate cases of sporadic Alzheimer's disease from control cases. Although the significance of Abeta for diagnosing Alzheimer's disease is controversial, high plasma concentrations of Abeta40 and low plasma concentrations of Abeta42 indicate an increased risk of dementia. SUMMARY: The usefulness of biomarkers in cerebrospinal fluid has been shown by numerous studies; this test is not commonly used, however, and blood biomarkers are therefore preferred. Increasing evidence shows that the plasma Abeta concentration may be a premorbid marker for the risk of Alzheimer's disease. It may be used for therapeutic monitoring, diagnosis of Abeta deposition in the brain, and also as a surrogate genetic marker to identify novel genetic determinants of Alzheimer's disease. A potential role of plasma Abeta concentration as a marker of incipient dementia warrants further investigation.     

Aluminum exposure and Alzheimer's disease

The regulatory agencies of the United States and Canada have placed aluminum on priority lists for research designed to fill data gaps relating to neurotoxicity. This is to create a factual basis for the establishment of health standards for drinking water. In this review, we consider evidence for a significant role for aluminum in AD. Aluminum has been implicated as a potential risk factor in Alzheimer's Disease (AD) and for elderly cognitive impairment by epidemiology studies of drinking water and a food study. Most people experience aluminum brain overload in the aging process. Aluminum levels over 20 times higher than those of a middle-aged group were found in a brain autopsy study of elderly persons, roughly correlating over the age period with densities of senile plaques and neurofibrillary tangles. Persons with AD have been found to experience increased absorption of aluminum and higher blood levels. More controversially, the majority of brain studies also show elevated aluminum levels, though there is disagreement over location of metal buildup. Clinical intervention to lower brain aluminum by chelation has slowed the progression of AD.     

阿尔茨海默病的生物学标志及其靶向治疗

阿尔茨海默病(AD)是临床最为常见的老年期神经变性疾病之一,其病理学特征表现为神经炎性斑[NPs,又称老年斑(SPs)]和神经原纤维缠结(NFTs)形成,基底节区和前脑胆碱能神经元大量缺失[1];临床主要表现为进行性认知损害和记忆力减退,致生活不能自理,直至死亡[2].     

Longitudinal changes of CSF biomarkers in Alzheimer's disease

Longitudinal changes of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have been studied, but there are few consistent conclusions and even less is known about their variation during the different stages of the disease. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. One hundred and thirty-one memory clinic patients [56 AD, 57 mild cognitive impairment (MCI), 10 other neurological disorders, eight unimpaired subjects] underwent a clinical follow-up with repeated Mini-Mental Status Examination (MMSE) tests and two lumbar punctures with a median interval of 3 years. Levels of CSF amyloid-β (Aβ)(42), tau, and p-tau-181 were measured using commercially available ELISA. Twenty-one of the MCI subjects progressed to AD, whereas 26 subjects remained stable and 56 subjects had AD already at the baseline. The subjects displaying the most rapid MMSE decline rate had the lowest baseline Aβ(42), highest tau, and highest p-tau-181 CSF concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau-181 concentration was seen in AD-AD patients (p = 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p = 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p = 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau-181 correlated with the MMSE decrease rate in AD subjects (r = 0.579, p < 0.001). The CSF Aβ(42) level decreased in the AD-AD group (decrease 11.9 pg/ml/year, p < 0.001). Concentrations of hyperphosphorylated tau decline in the late stages of the AD process. The decrease of p-tau-181 appears to correlate with cognitive functioning and probably reflects neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients during the preclinical stage of the disease.     

Cerebrospinal fluid proteomic biomarkers for Alzheimer's disease

OBJECTIVE: To find a panel of proteins in antemortem cerebrospinal fluid (CSF) that could be used to differentiate between samples from Alzheimer's disease (AD) patients and samples from healthy and neurological control subjects. METHODS: For a test cohort, antemortem CSF proteins from 34 AD and 34 non-AD patients were separated using two-dimensional gel electrophoresis. The resulting protein patterns were analyzed using the random forest multivariate statistical method. Protein spots of interest were identified using tandem time-of-flight mass spectrometry. A validation cohort consisting of CSF from 18 AD patients and 10 non-AD subjects was analyzed in a similar way. RESULTS: Using the test cohort, a panel of 23 spots was identified that could be used to differentiate AD and non-AD gels with a sensitivity of 94%, a specificity of 94%, and a predicted classification error rate of only 5.9%. These proteins are related to the transport of beta-amyloid, the inflammatory response, proteolytic inhibition, and neuronal membrane proteins. The 23 spots separately classified the validation cohort with 90% sensitivity (probable AD subjects), 83% specificity, and a predicted classification error rate of 14% in a blinded analysis. The total observed sensitivity is 93%, the total observed specificity is 90%, and the predicted classification error rate is 8.3%. INTERPRETATION: A panel of possible CSF biomarkers for AD has been identified using proteomic methods.     

Disease-specific adaptive immune biomarkers in Alzheimer's disease and related pathologies

Identification of disease-specific diagnostic and prognostic biomarkers allowing for an early characterization and accurate clinical follow-up of Alzheimer's disease (AD) patients is a major clinical objective. Increasing evidences implicate both humoral and cellular adaptive immune responses in the pathophysiology of AD. Such disease-related B- and T-cell responses constitute a promising source of potential specific early biomarkers. Among them, levels of anti-Aβ antibodies in the serum and/or cerebrospinal fluid of patients may correlate with AD progression, clinical presentation of the disease, and occurrence of associated pathologies related to cerebral amyloid angiopathy. In the same line, Aβ-specific T cell responses and immune regulatory populations implicated in their modulation appear to play a role in the pathophysiology of AD and cerebral amyloid angiopathy. Further characterization of both autoantibodies and T cell responses specific for disease-related proteins, i.e. Aβ and hyperphosphorylated Tau, will allow better deciphering their interest as early diagnostic and prognostic markers in AD. Biomarkers of adaptive immune responses specific for other pathological proteins may also apply to other neurological disorders associated with abnormal protein deposition.     

A case-control study on Alzheimer's disease and exposure to anesthesia

A retrospective hospital-based case-control study was performed with the aim to evaluate the association between exposure to anesthesia and Alzheimer's disease (AD). A total of 115 AD patients, 230 Parkinson's disease (PD) patients and 230 patients with non-degenerative neurological disease were studied. Each AD case was matched for sex, age (±3 years) and geographic area of residence with four controls (2 PD patients and 2 with other neurological disease). Information about exposure to general anesthesia and other variables was gathered through hospital records. No associations were found between the risk of AD and the exposure to anesthesia in the 1 and 5 years preceding disease onset, nor between the risk of AD and the number of surgical operations. A significant difference was observed between the mean age of AD patients and controls undergoing surgical procedures. The present study reveals a lack of association between exposure to general anesthesia and AD. Prospective epidemiological studies are needed in order to investigate levels of exposure to anesthesia, as well as any possible relationships between anesthetic exposure and genetic factors (e. g. APOEɛ4 genotype). Received: 25 October 2001 / Accepted in revised form: 31 January 2002     

Incorporating biomarkers into clinical drug trials in Alzheimer's disease

Incorporating biomarkers into clinical drug trials for Alzheimer's disease (AD) could 1) increase the homogeneity of patients through improved diagnosis, 2) establish surrogate outcome measures for drug efficacy, 3) test pharmacogenetic bases of drug response, and 4) verify proposed mechanisms of drug action. Among biological correlates of AD, those with the greatest potential to improve diagnostic accuracy are genetic abnormalities that cause AD or increase the risk of AD; characteristic changes in amyloid derivatives and tau and blood in CSF; and neuroimaging detection of brain atrophy and reduction in brain metabolism and blood flow. Although there are no AD biological markers that qualify as true surrogate endpoints in clinical drug trials, indices of brain atrophy show promise as a technique to track progression of dementia and as a measure of treatment efficacy. Anti-amyloid strategies for treatment are the leading candidates for the next generation of Alzheimer therapies. Predicted changes in amyloid derivative levels in CSF can help verify drug activity and illuminate the mechanism of action.     

Acetylcholinesterase and butyrylcholinesterase glycoforms are biomarkers of Alzheimer's disease

The identification of a biochemical marker in cerebrospinal fluid (CSF) that can discriminate between Alzheimer's disease (AD) and other dementia-causing diseases would be a major advance. Our previous studies have shown that the glycosylation of acetylcholinesterase (AChE) is altered in the post mortem brain and cerebrospinal fluid of AD patients. We have also found that the glycosylation of AChE is altered in lumbar CSF collected ante mortem. The change in glycosylation of AChE is very specific for AD and is not seen in many other neurological diseases including other dementias. The sensitivity of detection of AD using AChE glycosylation (60-80%) satisfactory diagnostic marker. However, more recently we have found that the glycosylation of the related enzyme butyrylcholinesterase (BuChE) is also altered in AD CSF. By combining the analysis of AChE glycosylation with that of BuChE glycosylation, improved sensitivity of detection is obtained. We propose that AChE and BuChE glycosylation may be of diagnostic value, especially when used in combination with other CSF markers such as Abeta or tau.     

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.