Biological Markers For Alzheimer's Disease Research Articles

AGEs RAGE Pathways: Alzheimer's Disease.

Neurofibrillary tangles and plaques containing tau serve as the biological markers for Alzheimer disease (AD) and pathogenesis is widely believed to be driven by the production and deposition of the β-amyloid peptide (Aβ). The β-amyloid peptide (Aβ) that results from the modification of the amyloid precursor protein (APP) by builds up as amyloid deposits in neuronal cells. Thus, a protein misfolding process is involved in the production of amyloid. In a native, aqueous buffer, amyloid fibrils are usually exceedingly stable and nearly insoluble. Although amyloid is essentially a foreign substance made of self-proteins, the immune system has difficulty identifying and eliminating it as such for unknown reasons. While the amyloidal deposit may have a direct role in the disease mechanism in some disease states involving amyloidal deposition, this is not always the case. Current research has shown that PS1 (presenilin 1) and BACE (beta-site APP-cleaving enzyme) have - and -secretase activity that increases β-amyloid peptide (Aβ). Wealth of data has shown that oxidative stress and AD are closely connected that causes the death of neuronal cells by producing reactive oxygen species (ROS). Additionally, it has been demonstrated that advanced glycation end products (AGEs) and β-amyloidal peptide (Aβ) together increase neurotoxicity. The objective of this review is to compile the most recent and intriguing data of AGEs and receptor for advanced glycation end products (RAGE) pathways which are responsible for AD.

Preclinical Alzheimer Disease and the Electronic Health Record: Balancing Confidentiality and Care.

Because information technologies are increasingly used to improve clinical research and care, personal health information (PHI) has wider dissemination than ever before. The 21st Century Cures Act in the United States now requires patient access to many components of the electronic health record (EHR). Although these changes promise to enhance communication and information sharing, they also bring higher risks of unwanted disclosure, both within and outside of health systems. Having preclinical Alzheimer disease (AD), where biological markers of AD are identified before the onset of any symptoms, is sensitive PHI. Because of the melding of ideas between preclinical and "clinical" (symptomatic) AD, unwanted disclosure of preclinical AD status can lead to personal harms of stigma, discrimination, and changes to insurability. At present, preclinical AD is identified mainly in research settings, although the consensus criteria for a clinical diagnosis may soon be established. There is not yet adequate legal protection for the growing number of individuals with preclinical AD. Some PHI generated in preclinical AD trials has clinical significance, necessitating urgent evaluations and longitudinal monitoring in care settings. AD researchers are obligated to both respect the confidentiality of participants' sensitive PHI and facilitate providers' access to necessary information, often requiring disclosure of preclinical AD status. The AD research community must continue to develop ethical, participant-centered practices related to confidentiality and disclosure, with attention to sensitive information in the EHR. These practices will be essential for translation into the clinic and across health systems and society at large.

Alzheimer disease and the periodontal patient: New insights, connections, and therapies.

Loss of cognitive function in the aging population, particular those with Alzheimer disease, presents unique challenges to health practitioners. For the dental practitioner these include management of periodontal diseases, caries, and other dental conditions in this special population. It is well established in the cognitively impaired patient that a lack of adherence to dental hygiene routines and professional care leads to increases in the prevalence and severity of these dental conditions, leading to increased loss of teeth. More recent evidence has indicated a possible role of the microbiota of dental plaque associated with periodontal diseases in the development and progression of Alzheimer disease, thereby supporting a two-way interaction of these two diseases. New therapies are needed to address the potential upstream events that may precede overt signs of Alzheimer disease. One of these approaches would be to target these various bacterial, viral, and other microbial pathogens associated with periodontal disease that can translocate into the bloodstream and then to distal sites, such as the brain. Such microbial translocation would lead to local inflammation and buildup of the hallmark signs of Alzheimer disease, including amyloid beta deposits, tau fragmentation and tangles, breakdown of host protective molecules, such as the apolipoproteins, and neuron toxicity. In this review, evidence for the biological basis of the role of the periodontal disease microflora on the initiation and progression of Alzheimer disease will be presented with a focus on the potential role of the keystone pathogen Porphyromonas gingivalis with its family of gingipain enzymes. The various mechanisms for which P.gingivalis gingipains may contribute to the initiation and progression of Alzheimer disease are presented. Small-molecule inhibitors of these gingipains and their effects on reducing biological markers of Alzheimer disease may have beneficial effects for the initiation and progression of loss of cognitive function in Alzheimer disease. In addition to these targeted therapies for specific periodontal pathogens, considerations for the dental practitioner in applying more general approaches to reducing the periodontal plaque microflora in the management of the cognitively impaired patient are discussed for this special population.

Alzheimer Disease Cerebrospinal Fluid Biomarkers Moderate Baseline Differences and Predict Longitudinal Change in Attentional Control and Episodic Memory Composites in the Adult Children Study.

Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms, and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within 2 years of the initial assessment to collect cerebrospinal fluid (CSF) and amyloid tracer Pittsburgh compound-B scan for amyloid imaging. Results indicated that attentional control was correlated with levels of Aβ42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. These results indicate that measures of attentional control and episodic memory can be used to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change.

Let Food Be Thy Medicine: Diet, Nutrition, and Biomarkers' Risk of Alzheimer's Disease.

Epidemiological evidence linking diet-one of the most important modifiable lifestyle factors-and risk of Alzheimer's disease (AD)-the most common cause of dementia-is rapidly increasing. However, the biological mechanisms underlying the relationship between dietary nutrients, brain aging, and risk of AD are largely unexplored. Recent studies using brain imaging and biological markers of AD have begun to clarify how diet and nutrition modulate risk of AD in cognitively normal individuals, especially those at increased genetic risk. Such knowledge is critical prior to implementing dietary recommendations for prevention and treatment of disease.

Autoantibodies to GM1 and GQ1bα are not biological markers of Alzheimer's disease.

A few studies have reported the association of autoantibodies to GM1 or GQ1bα with Alzheimer's disease (AD) or vascular dementia. Here we investigated whether patients with AD or vascular dementia had high titers of the anti-ganglioside antibodies. Sera were obtained from patients with AD (n = 22), vascular dementia (n = 14), Guillain-Barré syndrome, and multifocal motor neuropathy as well as normal controls. Enzyme-linked immunosorbent assay showed titers of IgG and IgM anti-GM1, anti-GQ1bα, and anti-GT1aα antibodies did not differ among AD, vascular dementia, and normal controls, and being remarkably lower than those in Guillain-Barré syndrome and multifocal motor neuropathy. The anti-ganglioside antibodies are not biological markers of AD.

EPA-0381 – Preliminary studies on cerebrospinal fluid of patient with alzheimer's disease using peptide microarray

The recently published diagnotic criteria of Alzheimer's disease (AD) includes biological markers (determination of b-amyloid 1-42 (Ab), tau and phospho-tau) from cerebrospinal fluid (CSF), but their positive predictive value proved low, therefore a new biomarker indentification is needed. Apoptosis plays crucial role in AD pathomechanism. Ab interacts with mitochondrial proteins causing oxidative stress. That induces the impairment of energy metabolism promoting tau phosphorylation indicating apoptosis. The purpose of this study was to identify pathognostic and apoptotic proteins in the CSF of AD patients. Pooled CSF samples of 5x5 AD patients and 5x5 controls were used. ELISAs were performed to determine the concentrations of Ab, tau and phospho-tau. 10 ultrasensitive slides of peptide microarrays with 653 antigens were used. If the ratio of technical repeats of AD and control samples was under 0.65 that meant decreased protein concentration. Apolipoprotein D (0,62), DNA polymerase gamma (0,51), parkin (0,58) and methylated-DNA-protein-cysteine methyltransferase (0,56) showed decreased concentration in AD in four chip pairs. The concentration of cyclin-dependent kinase 5 (0,45), granzyme B (0,37) and prostate apoptosis response 4 proteins (0,60) reduced in three chip pairs. These data contribute to the database that will be used to elucidate the new biological markers for AD. Our findings may have implications for both the diagnosis and the understanding of AD pathogenesis, by defining a patient-specific signature to diagnose AD. Using these 7 biomarkers to identify AD prior to the onset of clinical symptoms and associated with neuronal loss enables novel clinical trial design and early mechanismbased therapeutic intervention. This study was supported by grants from OTKA (83667), and the Hungarian Ministry of Education and Culture (TÁMOP 4.2.2-08/1-2008-0002, 4.2.1./B-09/1/KONV-2010-0005-3, 4.2.4.A/2-11-1-2012-0001).

When Does Alzheimer Disease Start

The pathological process of Alzheimer disease (AD) begins before the clinical symptoms manifest. To identify the timing and stages of this process, researchers examined biological markers of AD in 128 individuals who had a parent with dominantly inherited AD (carriers of the APP , PSEN1 , or PSEN2 gene mutation). The researchers tested the participants for carrier status of the relevant gene. Using the affected parent's age at onset and the participant's age at …

Are Guidelines Needed for the Diagnosis and Management of Incipient Alzheimer's Disease and Mild Cognitive Impairment?

Current research is aiming to push the boundaries of the point at which a diagnosis of Alzheimer Disease (AD) can be made. Clinical syndromes such as Mild Cognitive Impairment (MCI) and various clinical and biological markers of AD may help to identify people in the early stage of AD, before a full dementia syndrome is present. In the first part of this paper, we discuss whether MCI represents incipient AD, and examine some of the methods currently used in research to identify AD patients in the preclinical phase. In the second part, we discuss whether specific guidelines are needed for the diagnosis and management of MCI and incipient AD, and consider the potential impact of this on clinical practice and public health from the perspective of patients, caregivers, and healthcare providers.

A multicenter 1 H-MRS study of the medial temporal lobe in AD and MCI

The need for biological markers of Alzheimer disease (AD) is constantly increasing. Proton magnetic resonance spectroscopy ((1)H-MRS) studies have provided consistent evidence for a reduction of the neuronal marker N-acetylaspartate (NAA) in patients with AD. Within the German Competence Network on Dementia, we conducted a (1)H-MRS study in patients with mild dementia and mild cognitive impairment (MCI) at four sites to investigate the multicenter feasibility of (1)H-MRS. In total, 130 patients with dementia (98 AD, 32 non-AD), 136 subjects with MCI (70 of AD type, 66 of non-AD type), and 45 unimpaired control subjects were included. Single-volume (1)H-MRS of the left medial temporal lobe was performed at long and short echo times. Metabolites were quantified and metabolic ratios were determined. We found a significant reduction of NAA concentration in patients with AD as compared to healthy volunteers and compared to patients with MCI of AD type. NAA/Cr (creatine/phosphocreatine) was also lower in patients with AD compared to control subjects. NAA, choline compounds, and Cr were lower in patients with AD compared to patients with non-AD dementia. We demonstrated the multicenter feasibility of proton magnetic resonance spectroscopy ((1)H-MRS) of the medial temporal lobe in mild dementia and mild cognitive impairment, which is a prerequisite for the application of (1)H-MRS in large-scale clinical trials. Since the concentration measures of the metabolites are adjusted for brain tissue volume, these findings are indicators of biochemical pathology beyond brain atrophy.

Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment

Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease (AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse model of AD. We also assessed brain content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Performance was alike in wild-type and APP23 animals in the radial maze. In contrast, performance in the complex maze was better in wild-type than APP23 animals. Contrary to the wild-type, hippocampal BDNF levels decreased on training in APP23 animals. Hippocampal and frontal cortex NGF levels in APP23 animals correlated with the time to solve the complex maze, but correlated inversely with escape time in wild-type animals. NT-3 levels were alike in wild-type and APP23 animals and were unchanged even after training. Both types of mazes depend on hippocampal integrity to some extent. However, according to the cognitive mapping theory of spatial learning, the complex maze because of the increased complexity of the environment most likely depends more strongly on preserved hippocampal function than the radial maze in the working memory configuration applied here. Greater impairment in complex maze performance than in radial maze performance thus resembles the predominant affliction of the loss of hippocampal function in human AD. NGF and BDNF levels on maze learning are different in wild-type and transgenic animals, indicating that biological markers of AD may be altered on challenge even though equilibrium levels are alike.

Circulating Levels of Soluble Receptor for Advanced Glycation End Products in Alzheimer Disease and Vascular Dementia

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. To investigate the role of sRAGE as a biological marker for Alzheimer disease and vascular dementia. Cross-sectional study of 152 patients with a clinical diagnosis of Alzheimer disease, 91 with vascular dementia and 161 control subjects. Plasma levels of sRAGE. 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). 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.

Binding of copper (II) ion to an Alzheimer's tau peptide as revealed by MALDI‐TOF MS, CD, and NMR

The tau protein plays an important role in some neurodegenerative diseases including Alzheimer's disease (AD). Neurofibrillary tangles (NFTs), a biological marker for AD, are aggregates of bundles of paired helical filaments (PHFs). In general, the alpha-sheet structure favors aberrant protein aggregates. However, some reports have shown that the alpha-helix structure is capable of triggering the formation of aberrant tau protein aggregates and PHFs have a high alpha-helix content. In addition, the third repeat fragment in the four-repeat microtubule-binding domain of the tau protein (residues 306-336: VQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQ, according to the longest tau protein) adopts a helical structure in trifluoroethanol (TFE) and may be a self-assembly model in the tau protein. In the human brain, there is a very small quantity of copper, which performs an important function. In our study, by means of matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopy, the binding properties of copper (II) ion to the R3 peptide derived from the third repeat fragment (residues 318-335: VTSKCGSLGNIHHKPGGG) have been investigated. The results show that copper ions bind to the R3 peptide. CD spectra, ultraviolet (UV)-visible absorption spectra, and MALDI-TOF MS show pH dependence and stoichiometry of Cu2+ binding. Furthermore, CD spectra and NMR spectroscopy elucidate the copper binding sites located in the R3 peptide. Finally, CD spectra reveal that the R3 peptide adopts a mixture structure of random structures, alpha-helices, and beta-turns in aqueous solutions at physiological pH. At pH 7.5, the addition of 0.25 mol eq of Cu2+ induces the conformational change from the mixture mentioned above to a monomeric helical structure, and a beta-sheet structure forms in the presence of 1 mol eq of Cu2+. As alpha-helix and beta-sheet structures are responsible for the formation of PHFs, it is hypothesized that Cu2+ is an inducer of self-assembly of the R3 peptide and makes the R3 peptide form a structure like PHF. Hence, it is postulated that Cu2+ plays an important role in the aggregation of the R3 peptide and tau protein and that copper (II) binding may be another possible involvement in AD.

Cerebral glucose metabolism, cerebrospinal fluid-β-amyloid 1–42 (CSF-Aβ42), tau and apolipoprotein E genotype in long-term rivastigmine and tacrine treated Alzheimer disease (AD) patients

We evaluated cerebral glucose metabolism (CMRglc) and cerebrospinal fluid (CSF) levels of tau and β-amyloid 1–42 (Aβ42), in relation to apolipoprotein E (ApoE) genotype, in patients with mild Alzheimer disease (AD) treated with rivastigmine ( n=11) and tacrine ( n=16) for 1 year; and two untreated AD groups. The rivastigmine-treated AD patients showed a significant increase in CMRglc as compared to both tacrine-treated and untreated AD subjects. The rivastigmine-treated AD group showed no change in CSF-tau levels after 1 year, while in contrast a significant increase as seen in tacrine-treated and untreated AD patients. The CSF-tau changes were mainly seen in ApoE ϵ4 carriers. There was no significant change in Aβ42 after 1-year treatment with either rivastigmine or tacrine. This study shows that the two long-term cholinesterase inhibitor treatments exert different effects on biological markers for AD.

Dementia--causes, diagnosis, treatment, and care

The prevalence of dementia in the elderly (65 years old and over) was estimated at 6.3% (men 5.8%, women 6.7%) in Japan in 1985. Epidemiological studies done in several prefectures in 1989 and later showed a tendency for patients with Alzheimer's disease (AD) to outnumber those with vascular dementia (VD); the VD/AD ratio was less than 1.0 in over half of the surveys. A pathologic study (Kosaka 1996) of 79 patients with dementia revealed that AD was more common than VD, although clinical diagnoses were the reverse, which indicated that VD is still overdiagnosed in Japan. Diffuse Lewy body disease was observed in 15% of those patients without correct clinical diagnosis. Many biological markers for AD have been reported. We used 1H-magnetic resonance spectroscopy of the brain and found that the ratio of N-acetyl aspartate to creatine in AD patients was significantly smaller than that in age-matched controls without dementia. Based on genetic studies, AD is classified into five types. These are related to chromosomes 14 (presenilin-1), 21 (beta APP gene), 1 (presenilin-2), 19 (epsilon 4 alleles), and other. The causes of most sporadic cases remain unclear. Tacrine is the only drug authorized in the U.S.A. for treatment of AD, but it is not used in Japan because of its side effects. Many other drugs to treat dementia are now in nationwide clinical trials although only four are in phase III. Therefore, rehabilitation therapy is mandatory and details of that therapy should be individualized. A new system of public insurance for nursing care may be implemented by the government.

Elevated Levels of the Endosomal‐Lysosomal Proteinase Cathepsin D in Cerebrospinal Fluid in Alzheimer Disease

Lysosomal hydrolases are normally intracellular enzymes but are abundant extracellularly within senile plaques in Alzheimer disease and in other conditions where beta-amyloid accumulates. To examine whether acid hydrolases released from abnormal hydrolase-laden neurons are detectable in CSF, we measured levels of the major aspartic proteinase of lysosomes, cathepsin D (Cat D), in ventricular CSF collected after death from 30 patients with Alzheimer disease, 14 patients with Huntington disease, and seven patients with other neurodegenerative diseases. The levels of Cat D-immunoreactive protein, expressed as micrograms per milliliter of protein, determined by western blot immunoassay using a polyclonal antiserum against human brain Cat D, were more than fourfold higher in the Alzheimer patients than in the other patient groups (p < 0.0005). Cat D activity, assayed separately against [14C]methemoglobin at pH 3.2, was also significantly elevated but less than Cat D content. The lower specific activity of Cat D in Alzheimer CSF therefore indicated that the abnormally accumulated Cat D included a high proportion of inactive enzyme. These results indicate that abnormal Cat D release from affected neurons into the extracellular space is an active, ongoing process in Alzheimer brain. In addition, the levels of this enzyme and possibly other lysosomal hydrolases in CSF may prove to be useful biological markers of Alzheimer disease.