amyloid-beta-peptides and Dementia

According to the latest revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) (NINCDS-ADRDA) diagnostic criteria for Alzheimer's disease dementia of the National Institute on Aging and Alzheimer Association, the confidence in diagnosing mild cognitive impairment (MCI) due to Alzheimer's disease dementia is raised with the application of biomarkers based on measures in the cerebrospinal fluid (CSF) or imaging. These tests, added to core clinical criteria, might increase the sensitivity or specificity of a testing strategy. However, the accuracy of biomarkers in the diagnosis of Alzheimer's disease dementia and other dementias has not yet been systematically evaluated. A formal systematic evaluation of sensitivity, specificity, and other properties of plasma and CSF amyloid beta (Aß) biomarkers was performed.. To determine the accuracy of plasma and CSF Aß levels for detecting those patients with MCI who would convert to Alzheimer's disease dementia or other forms of dementia over time.. The most recent search for this review was performed on 3 December 2012. We searched MEDLINE (OvidSP), EMBASE (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science and Conference Proceedings (ISI Web of Knowledge), PsycINFO (OvidSP), and LILACS (BIREME). We also requested a search of the Cochrane Register of Diagnostic Test Accuracy Studies (managed by the Cochrane Renal Group).No language or date restrictions were applied to the electronic searches and methodological filters were not used so as to maximise sensitivity.. We selected those studies that had prospectively well defined cohorts with any accepted definition of cognitive decline, but no dementia, with baseline CSF or plasma Aß levels, or both, documented at or around the time the above diagnoses were made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing plasma and CSF Aß biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's dementia diagnosis, for example the NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria.. We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create standard two by two tables. Two independent assessors performed quality assessment using the QUADAS-2 tool. Where data allowed, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic (ROC) curve.. Alzheimer's disease dementia was evaluated in 14 studies using CSF Aß42. Of the 1349 participants included in the meta-analysis, 436 developed Alzheimer's dementia. Individual study estimates of sensitivity were between 36% and 100% while the specificities were between 29% and 91%. Because of the variation in assay thresholds, we did not estimate summary sensitivity and specificity. However, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary ROC curve. At the median specificity of 64%, the sensitivity was 81% (95% CI 72 to 87). This equated to a positive likelihood ratio (LR+) of 2.22 (95% CI 2.00 to 2.47) and a negative likelihood ratio (LR-) of 0.31 (95% CI 0.21 to 0.48).The accuracy of CSF Aß42 for all forms of dementia was evaluated in four studies. Of the 464 participants examined, 188 developed a form of dementia (Alzheimer's disease and other forms of dementia).The thresholds used were between 209 mg/ml and 512 ng/ml. The sensitivities were between 56% and 75% while the specificities were between 47% and 76%. At the median specificity of 75%, the sensitivity was estimated to be 63% (95% CI 22 to 91) from the meta-analytic model. This equated to a LR+ of 2.51 (95% CI 1.30 to 4.86) and a LR- of 0.50 (95% CI 0.16 to 1.51).The accuracy of CSF Aß42 for non-Alzheimer's disease dementia was evaluated in three studies. Of the 385 participants examined, 61 developed non-Alzheimer's disease dementia. Since there were very few studies and considerable variation between studies, the results were not meta-analysed. The sensitivities were between 8% and 63% while the specificities were between 35% and 67%.Only one study examined the accuracy of plasma Aß42 and the plasma Aß42/Aß40 ratio for Alzheimer's disease dementia. The sensitivity of 86% (95% CI 81 to 90) was the same for both tests while the specificities were 50% (95% CI 44 to 55) and 70% (95% CI 64 to 75) for plasma Aß42 and the plasma Aß42/Aß40 ratio respectively. Of the 565 participants examined, 245 developed Alzheimer's dementia and 87 non-Alzheimer's disease dementia.There was substantial heterogeneity between studies. The accuracy of Aß42 for the diagnosis of Alzheimer's disease dementia did not differ significantly (P = 0.8) between studies that pre-specified the threshold for determining test positivity (n = 6) and those that only determined the threshold at follow-up (n = 8). One study excluded a sample of MCI non-Alzheimer's diseas. The proposed diagnostic criteria for prodromal dementia and MCI due to Alzheimer's disease, although still being debated, would be fulfilled where there is both core clinical and cognitive criteria and a single biomarker abnormality. From our review, the measure of abnormally low CSF Aß levels has very little diagnostic benefit with likelihood ratios suggesting only marginal clinical utility. The quality of reports was also poor, and thresholds and length of follow-up were inconsistent. We conclude that when applied to a population of patients with MCI, CSF Aß levels cannot be recommended as an accurate test for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Dementia; Disease Progression; Humans; Peptide Fragments; Sensitivity and Specificity

At present, there may be over 210,000 people with Down syndrome (DS) over the age of 55 in the United States (US) who have significant needs for augmented services due to circumstances related to ordinary and/or pathological aging. From 1979 through 2003, the birth prevalence of DS rose from 9.0 to 11.8 (31.1%) per 10,000 live births in 10 representative US regions. This increase, largely due to women conceiving after age 35, portends an ever-growing population of people with DS who may be subject to pathogenic aging. Whereas Trisomy 21 is one of the most widespread genetic causes of intellectual disability (ID), it still is one of the least understood of all genetic ID syndromes. While longevity in people with DS has improved appreciably in as modest a period as 30 years, age-specific risk for mortality still is considerably increased compared both with other people with ID or with the typically developing population. The penetrance of the phenotype is widely distributed, even though a consistent genotype is assumed in 95% of the cases. Some, but not all body systems, exhibit signs of premature or accelerated aging. This may be due to both genetic and epigenetic inheritance. We now know that the long-term outcome for people with DS is not as ominous as once contemplated; a number of people with DS are living into their late 60s and 70s with few if any major signs of pathogenic aging. Alzheimer's disease (AD), a devastating disease that robs a person of their memory, abilities and personality, is particularly common in elder adults with DS, but is not a certainty as originally thought, some 20% to 30% of elder adults with DS might never show any, or at most mild signs of AD. DS has been called a mature well-understood syndrome, not in need of further research or science funding. We are only beginning to understand how epigenetics affects the phenotype and it may be feasible in the future to alter the phenotype through epigenetic interventions. This chapter is divided into two sections. The first section will review typical and atypical aging patterns in somatic issues in elder adults with DS; the second section will review the multifaceted relationship between AD and DS.

Topics: Adult; Aging; Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Dementia; Donepezil; Down Syndrome; Female; Humans; Incidence; Indans; Intellectual Disability; Male; Metabolic Syndrome; Middle Aged; Nootropic Agents; Oxidative Stress; Peptide Fragments; Phenotype; Piperidines; Prevalence; Telomere Shortening; Treatment Outcome; United States

We wanted to further study amyloid Abeta protein alterations in non-AD neurodegenerative diseases. Cerebrospinal fluid concentrations of the amyloid Abeta protein with 40 (Abeta40) and 42 (Abeta42) amino acid residues were measured in eleven patients with frontotemporal dementia (FTD). Abeta40 and Abeta42 concentrations were related to the degree of frontal lobe atrophy as assessed with MRI volumetry. Abeta40 concentrations showed a statistically significant linear correlation with degree of frontal lobe atrophy (r = -0.77, p<0.02). Similar results have not been found in previous studies of CSF Abeta40 concentrations and atrophy in patients with AD which suggest that the role of Abeta40 differs between the pathological processes of FTD and AD.

Topics: Aged; Amyloid beta-Peptides; Dementia; Female; Frontal Lobe; Humans; Linear Models; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments

TAR DNA-binding protein-43 (TDP-43) and neurofilament light chain (NfL) are promising fluid biomarkers of disease progression for various dementia.. We would explore whether blood levels of NfL and TDP-43 could predict the long-term progression to dementia, and the relationship of TDP-43 levels between cerebrospinal fluid (CSF) and blood.. A total of 86 non-dementia elderly received 7-year follow-up, and were divided into 49 stable normal control (NC)/mild cognitive impairment (MCI) subjects, 19 subjects progressing from NC to MCI, and 18 subjects progressing from NC/MCI to dementia. Blood TDP-43 and NfL levels, and cognitive functions were measured in all subjects. Furthermore, another cohort of 23 dementia patients, including 13 AD and 10 non-AD patients received blood and CSF measurements of TDP-43.. In cohort 1, compared to stable NC/MCI group, there were higher levels of blood TDP-43 at baseline in subjects progressing from NC/MCI to dementia. The combination of baseline blood TDP-43 levels with demographics including age, education, and diabetes had the detection for dementia occurrence. Baseline blood levels of NfL are negatively associated with cognitive function at 7-year follow-up. In cohort 2, we found there were no relationship between CSF and blood levels of TDP-43. Moreover, the levels of TDP-43 in CSF was positively associated with the age of patients, especially in AD group.. Single blood TDP-43 could not estimate dementia occurrence; however, TDP-43 combined with demographics has the predictive effect for dementia occurrence and NfL level is associated with a decrease of cognitive function.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Case-Control Studies; Cognitive Dysfunction; Dementia; Disease Progression; DNA-Binding Proteins; Educational Status; Female; Humans; Independent Living; Male; Middle Aged; Neurofilament Proteins; Peptide Fragments; Phosphorylation; Risk Assessment; tau Proteins

The ratio of β-amyloid 1-42 (Aβ42) to Aβ40 in cerebrospinal fluid (CSF) may be useful for evaluating Alzheimer disease (AD), but quantification is limited by factors including preanalytical analyte loss. We developed an LC-MS/MS assay that limits analyte loss. Here we describe the analytical characteristics of the assay and its performance in differentiating patients with AD from non-AD dementia and healthy controls.. The assay had a reportable range of 100 to 25000 pg/mL, a limit of quantification of 100 pg/mL, recoveries between 93% and 111%, and intraassay and interassay CV <15% for both peptides. An Aβ42/Aβ40 ratio cutoff of <0.16 had a clinical sensitivity of 78% for distinguishing patients with AD from non-AD dementia (clinical specificity, 91%) and from healthy controls (clinical specificity, 81%). The Aβ42/Aβ40 ratio decreased significantly (. This assay can be used to determine Aβ42/Aβ40 ratios, which correlate with the presence of AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Chromatography, Liquid; Cognitive Dysfunction; Dementia; Female; High-Throughput Screening Assays; Humans; Male; Middle Aged; Peptide Fragments; Sensitivity and Specificity; Tandem Mass Spectrometry; tau Proteins

Accumulating evidence suggests that disparate pathways from systemic metabolism to retinoic acid/vitamin A signaling can contribute to Alzheimer's disease (AD) pathobiology. Retinol binding protein 4 (RBP4) is an adipocyte-secreted hormone (adipokine) that regulates insulin signaling and is also a key transporter of retinoic acid and its derivatives. While earlier studies found alterations in the brain and cerebrospinal fluid (CSF) levels of RBP4 in later stages of AD, it is not known if circulating RBP4 is altered in preclinical AD or if it can be a useful biomarker for cognitive decline and dementia. In this study, we used ELISA to measure plasma RBP4 levels in cognitively normal individuals (Clinical Dementia Rating, CDR 0). Subjects with preclinical AD were identified by previously established CSF criteria (preclinical AD: 20 men, 18 women; control: 45 men, 73 women). Plasma RBP4 levels were similar between preclinical AD and control subjects in men (preclinical AD: 30.0±7.4 μg/mL; control: 30.0±8.7 μg/mL; p = 0.97) and women (preclinical AD 30.9±7.9 μg/mL; control: 31.7±8.5 μg/mL; p = 0.72). Additionally, RBP4 levels were not related to body mass index or CSF AD biomarkers levels of amyloid-β42, tau, or phosphorylated tau. Baseline plasma RBP4 levels were not associated with the incidence of CDR ≥0.5, all-cause dementia, or AD diagnosis. Collectively, these results do not support peripheral RBP4 as a clinical biomarker or therapeutic target in the early stages of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Dementia; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Male; Negative Results; Peptide Fragments; Retinol-Binding Proteins, Plasma; tau Proteins

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in idiopathic normal pressure hydrocephalus (iNPH) with the aim of a better differential diagnosis, but the pathophysiological mechanisms underlying CSF biomarker changes and the relationship between biomarker levels and clinical variables are still a matter of debate. We evaluated CSF amyloid-β (Aβ)42 and Aβ40, total (t)-tau, phosphorylated (p)-tau, total prion protein (t-PrP), and neurofilament light chain protein (NfL) in healthy controls (n = 50) and subjects with iNPH (n = 71), Alzheimer's disease (AD) (n = 60), and several other subtypes of dementia (n = 145). Patients with iNPH showed significantly lower levels of Aβ42, Aβ40, t-tau, and p-tau compared to controls. Similarly, t-PrP values showed a trend toward lower levels in iNPH patients than in controls. At variance, NfL levels were increased in iNPH as in all other neurodegenerative dementias, with no significant difference between "pure" iNPH cases and those with vascular or AD comorbidities. The Aβ42/Aβ40 ratio showed higher diagnostic value than Aβ42 alone in the differential diagnosis between iNPH and AD. There were no clinically relevant associations between neuroimaging markers, scores at clinical and cognitive scales/tests, or rates of response at tap test and CSF biomarker results. In summary, the CSF biomarker signature in patients with iNPH is mainly characterized by reduced CSF concentrations of Aβ- and tau-related proteins. The assessment of CSF neurodegenerative biomarker profile in iNPH, including the Aβ42/Aβ40 ratio, contributes to the differential diagnosis with AD and other dementias but shows poor associations with clinical variables.

Topics: Aged; Amyloid beta-Peptides; Biomarkers; Cohort Studies; Dementia; Diagnosis, Differential; Female; Humans; Hydrocephalus, Normal Pressure; Italy; Male; Middle Aged; Neurofilament Proteins; Peptide Fragments; Prion Proteins; tau Proteins

The cerebrospinal fluid (CSF) biomarkers amyloid-β

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Dementia; Diagnosis, Differential; Female; Humans; Immunoassay; Male; Middle Aged; Peptide Fragments; Sex Factors

Low cerebrospinal fluid (CSF) levels of Aβ42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Aβ interacts with different brain pathologies early in the disease process is limited. We examined how CSF Aβ markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old.. To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia.. 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aβ42 and Aβ40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed.. In 85-year-olds without dementia, lower levels of both CSF Aβ42 and CSF Aβ40 were associated with WMLs. CSF Aβ42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aβ42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs.. Our findings may suggest that there is an interrelationship between Aβ and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aβ42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Aβ deposition than cortical degeneration.

Topics: Aged, 80 and over; Amyloid beta-Peptides; Biomarkers; Brain; Cohort Studies; Cross-Sectional Studies; Dementia; Female; Humans; Male; Peptide Fragments; Tomography, X-Ray Computed; White Matter

Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD).. To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD.. We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors.. Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume.. Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Brain; Dementia; Female; Germany; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Oxygen; Peptide Fragments; Prodromal Symptoms; Rest

Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.. To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers.. Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study.. NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects.. Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.

Topics: Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Biomarkers; Cattle; Clinical Chemistry Tests; Dementia; Humans; Peptide Fragments; Quality Control; Reference Standards; Serum Albumin, Bovine; Sodium Azide; tau Proteins; Time Factors; Tissue Preservation

There is a need to investigate biomarkers that are indicative of the progression of dementia in ethnic patient populations. The disparity of information in these populations has been the focus of many clinical and academic centers, including ours, to contribute to a higher success rate in clinical trials. In this study, we have investigated plasma biomarkers in amnestic mild cognitively impaired (aMCI) female patient cohorts in the context of ethnicity and cognitive status.. A panel of 12 biomarkers involved in the progression of brain pathology, inflammation, and cardiovascular disorders were investigated in female cohorts of African American, Hispanic, and White aMCI patients. Both biochemical and algorithmic analyses were applied to correlate biomarker levels measured during the early stages of the disease for each ethnicity.. We report elevated plasma Aβ. Overall, our data displayed novel differences in the plasma biomarkers of the aMCI female cohorts where the plasma levels of several biomarkers distinguished between each ethnicity at an early aMCI stage. Identification of these plasma biomarkers encourages new areas of investigation among aMCI ethnic populations, including larger patient cohorts and longitudinal study designs.

Topics: Aged; Aged, 80 and over; Algorithms; Amyloid beta-Peptides; Biomarkers; Black or African American; Chitinase-3-Like Protein 1; Cohort Studies; Cystatin C; Decision Trees; Dementia; Enzyme-Linked Immunosorbent Assay; Female; Hispanic or Latino; Humans; Intercellular Signaling Peptides and Proteins; Mental Status Schedule; Middle Aged; Peptide Fragments; Progranulins; White People

We used a novel approach to molecular quantification in standard fixed and embedded tissue to measure amyloid β 42 (Aβ(42)) and paired helical filament-τ (PHF-τ) in frontal, temporal, and parietal cortices from 325 consecutive brain autopsies collected as part of a population-based study of brain aging and incident dementia in the Seattle area. We observed significant effects of APOE ε4 on Aβ(42) levels in both diagnostic groups by disease stage and region. In contrast, we did not observe a significant effect of APOE ε4 on PHF-τ levels by disease stage in any region. Levels of Aβ(42) and PHF-τ in cerebral cortex were correlated more strongly in the Dementia group, and these measures had independent explanatory power for dementia beyond those of standard neuropathologic indices. Associations between Lewy body disease and Aβ(42) or PHF-τ levels and between Aβ(42) levels and microvascular brain injury suggested that these comorbid diseases enhanced the penetrance of Alzheimer disease. Our novel approach brings additional insights into the molecular pathogenesis of common causes of dementia and may serve as a platform for future studies pursuing associations between molecular changes in Alzheimer disease and genetic or environmental risk.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Analysis of Variance; Apolipoprotein E4; Autopsy; Cerebral Cortex; Community Health Planning; Dementia; Female; Genotype; Humans; Male; Peptide Fragments; Severity of Illness Index; tau Proteins

Polygonum cuspidatum Sieb. Et Zucc. (Polygonaceae) has been traditionally used in folk medicine to treat various diseases.. This study investigates the ameliorative effects of physcion 8-O-β-glucopyranoside (PSG) isolated from P. cuspidatum on learning and memory in dementia rats induced by Aβ1-40.. Dementia rats were prepared by intracerebroventricular injection of Aβ1-40. PSG (5, 10, 20, and 40 mg/kg/d, for 5 d) was administered orally. Ameliorative activity of PSG in dementia rats was evaluated by the Morris water maze (MWM) test, and its mechanisms were explored by evaluating AchE activity, levels of DA, NE, and 5-HT in hippocampus, and drebrin protein expressions in hippocampus.. Our results indicated that PSG (5, 10, 20, and 40 mg/kg/d) significantly inhibited the prolonged latency in dementia rats (p < 0.05), and inhibitory rates were 16.5, 22.7, 33.0, and 44.8% after 5 d of learning, indicating that PSG improves learning and memory of dementia rats. Furthermore, PSG significantly decreased AchE activity (10, 20, and 40 mg/kg/d; p < 0.05), increased 5-HT (20 and 40 mg/kg/d, p < 0.05), NE (10, 20, and 40 mg/kg/d; p < 0.05), and DA levels (5, 10, 20, and 40 mg/kg; p < 0.05) in the hippocampus. Additionally, PSG obviously decreased the Aβ contents in hippocampus (10, 20, and 40 mg/kg/d; p < 0.05), and up-regulated drebrin protein expressions (5, 10, 20, and 40 mg/kg/d; p < 0.05).. PSG can significantly enhance learning and memory in Aβ1-40-induced dementia rats, and the mechanisms may be related to increase levels of Ach, 5-HT, NE, and DA, decrease Aβ contents, and up-regulation of drebrin proteins in hippocampus.

Topics: Amyloid beta-Peptides; Animals; Dementia; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Emodin; Fallopia japonica; Male; Maze Learning; Memory; Monosaccharides; Peptide Fragments; Plant Roots; Rats; Rats, Sprague-Dawley; Reaction Time; Treatment Outcome

Tong Luo Jiu Nao (TLJN), a modern formula of Chinese medicine extracts on the basis of Traditional Chinese Medicine theory, has been used to treat dementia. The present study aimed to investigate its ameliorating effects on Aβ1-40-induced cognitive impairment in rats using a series of novel reward-directed instrumental learning (RDIL) tasks, and to determine its possible mechanism of action.. Rats were pretreated with TLJN extract (0.9 and 1.8 g/kg, p.o.) for 10 daysbefore surgery, and were trained to gain reward reinforcement by lever pressing at the meantime. Thereafter, rats received a bilateral microinjection of Aβ1-40 in CA1 regions of the hippocampus. Cognitive performance was evaluated with the goal directed (higher response ratio) and habit (visual signal discrimination and extinction) learning tasks, as well as on the levels of biochemical parameters and molecules.. Our findings first demonstrated that TLJN can improve Aβ1-40-induced amnesia in RDIL via enhancing the comprehension of action-outcome association and the utilization of cue information to guide behavior. Then, its ameliorating effects should attribute to the modulation of ERK/CaMKII/CREB signaling in the hippocampus.. TLJN can markedly enhance cognitions of Aβ1-40 microinjection animal model in adaptive behavioral tasks. It has the potential, possibly as complementary and alternative therapy, to prevent and/or delay the deterioration of cognitive impairment in AD.

Topics: Adaptation, Psychological; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cognition; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; Dementia; Disease Models, Animal; Drugs, Chinese Herbal; Feedback, Psychological; Hippocampus; Learning; Male; MAP Kinase Signaling System; Medicine, Chinese Traditional; Peptide Fragments; Phytotherapy; Rats, Wistar; Signal Transduction

Overexpression of the mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10, which is also known as the intracellular amyloid-β peptide (Aβ) binding protein) is observed in cortical or hippocampal regions of patients with Alzheimer's disease (AD). It appears that 17β-HSD10 may play a role in the pathogenesis of AD.. We investigated the possibility that levels of 17β-HSD10 in cerebrospinal fluid could be a prospective biomarker of AD.. We estimated the enzyme levels in 161 people (15 non-demented controls, 52 people with mild cognitive impairment (MCI), 35 people with probable AD, or 59 people with other types of dementia) and compared them with those of Aβ(1- 42), tau, and phospho-tau.. We found significantly higher levels of 17β-HSD10 in people with MCI due to AD (to 109.9% ), with AD (to 120.0% ), or with other types of dementia (to 110.9% ) when compared to the control group. The sensitivity of the new biomarker to AD was 80.0% , and the specificity was 73.3% (compared to controls) or 52.5-59.1% (compared to other types of dementia). Results of multiple linear regression and of correlation analysis revealed AD-mediated changes in links between 17β-HSD10 and Mini Mental State Examination score.. It seems that changes in 17β-HSD10 start many years before symptom onset, analogous to those in Aβ1 - 42, tau, or phospho-tau and that the levels are a relatively highly sensitive but unfortunately less specific biomarker of AD. A role of 17β-HSD10 overexpression in AD is discussed.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Age Factors; Aged; Amyloid beta-Peptides; Cognitive Dysfunction; Dementia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mental Status Schedule; Middle Aged; Peptide Fragments; ROC Curve; tau Proteins

Mitochondrial dysfunction occurs early in the course of several neurodegenerative diseases, and is potentially related to increased oxidative damage and amyloid-β (Aβ) formation in Alzheimer's disease. The goals of this study were to assess mtDNA sequence associations with dementia risk, 10-year cognitive change, and markers of oxidative stress and Aβ among 1089 African-Americans in the population-based Health, Aging, and Body Composition Study. Participants were free of dementia at baseline, and incidence was determined in 187 (18%) cases over 10 to 12 follow-up years. Haplogroup L1 participants were at increased risk for developing dementia (odds ratio = 1.88, 95% confidence interval = 1.23-2.88, p = 0.004), lower plasma Aβ42 levels (p = 0.03), and greater 10-year decline on the Digit Symbol Substitution Test (p = 0.04) when compared with common haplogroup L3. The p.V193I, ND2 substitution was associated with significantly higher Aβ42 levels (p = 0.0012), and this association was present in haplogroup L3 (p = 0.018) but not L1 (p = 0.90) participants. All associations were independent of potential confounders, including APOEε4 status and nuclear genetic ancestry. Identification of mtDNA sequence variation associated with dementia risk and cognitive decline may contribute to the development of new treatment targets and diagnostic tests that identify responders to interventions targeting mitochondria.

Topics: Aged; Amyloid beta-Peptides; Base Sequence; Biomarkers; Black or African American; Cognition; Cohort Studies; Dementia; DNA, Mitochondrial; Female; Follow-Up Studies; Genotype; Humans; Male; Neuropsychological Tests; Oxidative Stress; Peptide Fragments; Prospective Studies; Risk; Time Factors

Cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for the diagnosis of Alzheimer's disease (AD). Since interpretation of CSF profile requires the combination of three parameters, biological data are not always conclusive and isolated elevation of phosphorylated tau (P-tau) or reduction of amyloid-β (Aβ)42 alone can be observed. In these cases, Aβ42/Aβ40 ratio could be more relevant than Aβ42 absolute values by considering inter-individual variations in the total amyloid load.. The objective of this study was to assess the use of Aβ42/Aβ40 ratio to improve the accuracy of biological conclusions in the diagnosis of patients with ambiguous CSF Aβ42 or tau results.. Among 386 lumbar punctures analyzed in the lab in 2 years, 122 showed ambiguous biological data that were completed by CSF Aβ40 quantification and Aβ42/Aβ40 ratio calculation. A biological conclusion was then made using 0.05 as the Aβ42/Aβ40 ratio cut-off.. Our results showed that one-third of the biological profiles of patients with atypical dementia were ambiguous. The addition of Aβ42/Aβ40 ratio increased the proportion of interpretable biological profiles from 69% to 87%, without changing the conclusion when usual biomarkers (Aβ42 and P-tau) were concordant.. Our results support the use of the Aβ42/Aβ40 ratio in addition to the usual CSF AD biomarkers for patients with ambiguous biological profiles. This method could be specifically directed to this population in order to improve the level of certainty for clinical routine practice.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Dementia; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Peptide Fragments; Phosphorylation; Spinal Puncture; tau Proteins; Young Adult

We validated the utility of SPM8 plus DARTEL (VSRAD) combined with magnetic resonance spectroscopy (1H MRS) as an adjunct screening technique for dementia due to Alzheimer's disease (AD). We examined the posterior cingulate gyri of 228 subjects using VSRAD and 1H MRS in addition to conventional cerebrospinal fluid biomarkers at baseline. At the 3-year follow-up, the 228 subject were classified as follows: 93 healthy subjects, 42 MCI-non-converters (MCI-NC), 25 MCI-converters to AD (MCI-C), 44 AD, 8 dementia with Lewy bodies (DLB), 5 normal pressure hydrocephalus, and 11 patients with other neurological diseases. Our results demonstrated that subjects with increased medial temporal atrophy (MTA) severity on VSRAD, increased Cho/Cr, MI/Cr ratio, and decreased NAA/Cr and NAA/MI ratio on 1H MRS at baseline were at risk of dementia due to AD. Receiver operating characteristic analysis showed that severity of MTA and the NAA/MI ratio distinguished patients with AD and MCI-C from controls. Furthermore, the 118 subjects without dementia and MTA showing only a decreased NAA/MI ratio at baseline developed to MCI-C, AD, and DLB 3 years later. 1H MRS detected biochemical abnormalities preceding brain atrophy and cognitive decline. VSRAD combined with 1H MRS may be routinely applied to screen for MCI/AD and prodromal AD in clinical practice.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aspartic Acid; Brain; Choline; Dementia; Disease Progression; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Retrospective Studies; Tritium

Amyloid-β (Aβ) is known as the most prominent core protein in Alzheimer's Disease (AD) senile plaques. Although research has focused mainly on Aβ40 and Aβ42 as potential cerebrospinal fluid (CSF) biomarkers, a range of Aβ peptides with variable lengths has been demonstrated in the brains and CSF of AD patients. Recently, it has been found that the Aβ43 peptide may be more abundant than previously assumed, could therefore play an important role in AD pathophysiology, and hence also function as putative biomarker. In this study the value of CSF Aβ43 in AD diagnosis was investigated. Aβ43 levels in CSF were highly correlated with Aβ42 levels. Furthermore, in differentiation of AD from nondemented controls and from patients with Lewy body dementia and frontotemporal dementia, Aβ43 had an equal diagnostic value as Aβ42, both as a single biomarker and in combination with total and phosphorylated tau. In conclusion, quantification of Aβ43 in CSF does not add novel diagnostic information to the differential diagnosis of AD compared to existing biomarkers.

Topics: Amyloid beta-Peptides; Dementia; Diagnosis, Differential; Humans; Peptide Fragments

It is assumed that the concentration of amyloid-β1-40 (Aβ1-40) in cerebrospinal fluid (CSF) reflects the total amount of Aβ protein in the brain and thus allows a better interpretation of inter-individual differences in Aβ quantity than the Aβ1-42 concentration. In this study, Aβ1-40 was added to the existing CSF biomarker panel of Aβ1-42, total tau (T-tau), and phosphorylated tau (P-tau181P) in order to test whether the accuracy of the differential dementia diagnosis improved. The concentration of Aβ1-40 (INNOTEST® β-amyloid(1-40) prototype version, Innogenetics NV, Belgium) and the other biomarkers (INNOTEST®) was determined in CSF samples from 80 Alzheimer's disease (AD) patients, 75 non-AD dementia patients, and 30 controls. A large proportion of the study population had autopsy-confirmed neurodegeneration (AD: 73/80 = 91%; non-AD: 38/75 = 51%). The levels of Aβ1-40 were decreased in AD (10856 ± 4745 pg/mL) and non-AD patients (10519 ± 4491 pg/mL) when compared to controls (14760 ± 7846 pg/mL) (p = 0.002 and p = 0.001). The Aβ1-42/Aβ1-40 ratio was significantly decreased in AD (0.043 ± 0.021) as compared to non-AD patients (0.064 ± 0.027; p < 0.001) and controls (0.053 ± 0.023; p < 0.001). In order to differentiate AD from non-AD patients, a decision tree was constructed. The diagnostic accuracy of the decision tree that contained Aβ1-42, Aβ1-40, P-tau181P, and the Aβ1-42/Aβ1-40 ratio was significantly better than the diagnostic accuracy (80% versus 74%) of the decision tree without Aβ1-40 and the Aβ1-42/Aβ1-40 ratio (p < 0.001). In conclusion, no difference in Aβ1-40 CSF levels was found between AD and non-AD patients, but adding CSF Aβ1-40 and the CSF Aβ1-42/Aβ1-40 ratio to a biomarker-based decision tree, might have an added value for discriminating AD from non-AD patients in case of intermediate CSF P-tau181P values.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Dementia; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Peptide Fragments; Phosphorylation; tau Proteins

The well-established core biomarkers used to identify Alzheimer's disease (AD) overlap with other dementia disorders such as dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). This study aimed to evaluate whether the cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42/Aβ1-40 ratio, measured by a novel method, could improve the differential diagnosis of AD, DLB and PDD.. CSF levels of Aβ1-40 and Aβ1-42 in patients with PDD, DLB, AD, Parkinson's disease and controls were analyzed using an amplified luminescent proximity homogenous immunoassay along with conventional immunoassays.. The CSF Aβ1-42/Aβ1-40 ratio increased discrimination of AD from PDD and DLB compared with either of the two Aβ biomarkers individually.. The use of the Aβ1-42/Aβ1-40 ratio could improve the differentiation of AD from PDD and DLB.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Antibodies; Area Under Curve; Biomarkers; Dementia; Diagnosis, Differential; Diagnostic and Statistical Manual of Mental Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoassay; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Peptide Fragments; Psychiatric Status Rating Scales

In view of the paucity of data on cerebrospinal fluid (CSF) biomarkers in Chinese patients, we evaluated the validity of tau, phosphorylated tau 181 (p-tau-181), amyloid β 42 (Aβ42), and Aβ40 proteins in Chinese patients with Alzheimer's disease (AD). We recruited 24 patients with AD, 12 nondemented controls, and 12 patients with non-AD dementia. We found the CSF levels of Aβ42, tau, p-tau, Aβ42-tau, and Aβ42-p-tau ratios, except the Aβ40 protein level, were significantly different among the 3 groups of patients. Patients with AD had higher levels of CSF tau and p-tau but lower levels of Aβ42 proteins, Aβ42-tau, and Aβ42-p-tau ratios than the nondemented controls. In the diagnosis of AD versus nondementia, the sensitivity and specificity of the ratios of Aβ42-tau and Aβ42-p-tau were 96% and 83% versus 92% and 83%, respectively. Only the Aβ42-p-tau ratio showed satisfactory sensitivity and specificity in the diagnosis of AD versus other dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Asian People; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Dementia; Female; Humans; Male; Middle Aged; Peptide Fragments; Phosphorylation; Pilot Projects; Sensitivity and Specificity; tau Proteins

Older adults with depression have an increased risk of developing dementia. Low plasma beta-amyloid 42 (Aβ42) and Aβ42/Aβ40 have emerged as promising biomarkers of dementia. The association between depression and plasma Aβ is unclear.. In this longitudinal study of 988 community-dwelling elders from the Health Aging and Body Composition study, depression was assessed with the Center for Epidemiologic Studies-Depression Scale 10-item version. We determined the association between Aβ42 and Aβ42/Aβ40 tertile and depression at baseline and over 9 years. We also stratified the models to determine if apolipoprotein E e4 allele status modified the associations.. Mean baseline age was 74.0 ± 3.0 years, 51 (5.2%) participants had depression, 545 (55.2%) were women, 531 (53.7%) were black, and 286 (30.7%) had one or more apolipoprotein E e4 allele. At baseline, there was no association between Aβ42/Aβ40 or Aβ42 and depression. Over 9 years, 220 (23.5%) participants developed depression. In adjusted Cox proportional hazards models, among those with one or more e4 allele, low Aβ42/Aβ40 was associated with an increased risk of developing depression over time (low 10.8% vs high 3.2%, hazard ratio = 2.38, 95% confidence interval: 1.15-4.92). Among those with no e4 allele, there was no association between Aβ42/Aβ40 and risk of depression over time (13.3% vs 17.5%, hazard ratio = 0.80, 95% confidence interval: 0.52-1.23; p value for interaction = .003).. The association between low plasma Aβ42/Aβ40 and increased risk of incident depression among those with one or more apolipoprotein E e4 allele implies a synergistic relationship similar to that found with dementia. Future work should investigate the interrelationships among plasma Aβ42/Aβ40, depression, and dementia.

Topics: Aged; Aging; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Cohort Studies; Dementia; Depression; Female; Humans; Longitudinal Studies; Male; Pennsylvania; Peptide Fragments; Prospective Studies; Risk Factors; Tennessee

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.

Topics: Adult; Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cohort Studies; Dementia; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peptide Fragments; Phosphorylation; Predictive Value of Tests; tau Proteins

Topics: Aging; Amyloid beta-Peptides; Dementia; Depressive Disorder, Major; Female; Humans; Male; Mental Disorders; Peptide Fragments

Alzheimer's disease (AD) can be classified based on the relative density of neurofibrillary tangles (NFTs) in the hippocampus and association cortices into three subtypes: typical AD, hippocampal-sparing AD (HpSp AD), and limbic-predominant AD (LP AD). AD subtypes not only have pathologic, but also demographic, clinical, and genetic differences. Neurofibrillary tangle-predominant dementia (NFTD), a disorder with NFTs relatively restricted to limbic structures, shares this feature with LP AD raising the possibility that NFTD is a variant of AD. The objective criteria for pathologic diagnosis of NFTD are not available. A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque (SP) counts in hippocampus and association cortices, analogous to that used to subtype AD. Moreover, we aimed to compare pathologic, demographic, clinical, and genetic features of NFTD (n = 18) with LP AD (n = 19), as well as the other AD subtypes, typical AD (n = 52) and HpSp AD (n = 17). Using digital microscopy, we confirmed that burden of phospho-tau (CP13) and of an NFT conformational epitope (Ab39) correlated with NFT densities and showed expected patterns across AD subtypes. HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity. On the other hand, cortical β-amyloid burden did not significantly differ between AD subtypes. Semi-quantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD, which was more frequent than LP AD. Compared to LP AD, NFTD had an older age at disease onset and shorter disease duration, as well as lower Braak NFT stage. NFTs and SPs on thioflavin-S fluorescent microscopy, as well as CP13, Ab39, and Aβ immunoreactivities were very low in the frontal cortex of NFTD, differentiating NFTD from AD subtypes, including LP AD. MAPT H1H1 genotype frequency was high (~70 %) in NFTD and LP AD, and similar to typical AD, while APOE ε4 carrier state was low in NFTD. While it shares clinical similarities with regard to female sex predominance, onset in advanced age, and a slow cognitive decline, NFTD has significant pathologic differences from LP AD, suggesting that it may not merely be a variant of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Brain; Dementia; Female; Humans; Male; Middle Aged; Neurofibrillary Tangles; Peptide Fragments; Plaque, Amyloid; Severity of Illness Index; tau Proteins

Adults with Down syndrome (DS) are at risk for developing Alzheimer's disease (AD). While plasma amyloid-β (Aβ) is known to be elevated in DS, its relationship to cognitive functioning is unknown. To assess this relationship, samples from two groups of subjects were used. In the first group, nondemented adults with DS were compared to: 1) a group of young and old individuals without DS and 2) to a group of patients with AD. Compared to these controls, there were significantly higher levels of plasma Aβ in nondemented adults with DS while AD patients showed lower levels of plasma Aβ. A larger second group included demented and nondemented adults with DS, in order to test the hypothesis that plasma Aβ may vary as a function of dementia and Apolipoprotein E (ApoE) genotype. Plasma Aβ levels alone did not dissociate DS adults with and without dementia. However, in demented adults with DS, ApoE4 was associated with higher Aβ40 but not Aβ42. After controlling for level of intellectual disability (mild, moderate, severe) and the presence or absence of dementia, there was an improved prediction of neuropsychological scores by plasma Aβ. In summary, plasma Aβ can help predict cognitive function in adults with DS independently of the presence or absence of dementia.

Topics: Adult; Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Biomarkers; Cohort Studies; Dementia; Down Syndrome; Female; Humans; Intellectual Disability; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests

To investigate the effect of neuregulin 1β (NRG1β) on the neuronal apoptosis and the expressions of Bcl-2 and Bax proteins in experimental dementia model rats.. Thirty adult healthy male Wistar rats were randomly divided into control group, model group and treated group consisting of 10 rats, respectively. The experimental dementia models were established by injecting beta-amyloid protein 1-40 (Aβ1-40) stereotactically into the left lateral ventricle, and treated by injecting NRG1β into right lateral ventricle. The cognitive capacity of rats was evaluated with Y-electric maze. The neuronal apoptosis was counted by TUNEL assay. The expressions of Bcl-2 and Bax were determined with immunohistochemistry assay and double immunofluorescence labeling.. The cognitive ability in model group rats decreased, along with the number of neuronal apoptosis and the expressions of Bcl-2 and Bax increased significantly than those in control group (P < 0.05). After treatment with NRG1β, the cognitive ability of rats improved, the number of neuronal apoptosis reduced and the expression of Bcl-2 increased while Bax decreased significantly than those in model group (P < 0.05).. NRG1β could inhibit neuronal apoptosis by regulating the expressions of Bcl-2/Bax to improve the capacity of learning and memory in experimental dementia rats.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; bcl-2-Associated X Protein; Dementia; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Humans; Injections, Intraventricular; Male; Maze Learning; Neuregulin-1; Neurons; Neuroprotective Agents; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar

An autosomal dominant mutation in the BRI2/ITM2B gene causes familial Danish dementia (FDD). Analysis of FDD(KI) mice, a mouse model of FDD genetically congruous to the human disease since they carry one mutant and one wild-type Bri2/Itm2b allele, has shown that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairments. BRI2 is a physiological interactor of Aβ-precursor protein (APP), a gene associated with Alzheimer disease, which inhibits processing of APP. Here, we show that APP/Bri2 complexes are reduced in synaptic membranes of FDD(KI) mice. Consequently, APP metabolites derived from processing of APP by β-, α- and γ-secretases are increased in Danish dementia mice. APP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for APP metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that APP and BRI2 functionally interact, and that the neurological effects of the Danish form of BRI2 only occur when sufficient levels of APP are supplied by two alleles. This evidence establishes a pathogenic sameness between familial Danish and Alzheimer's dementias.

Topics: Adaptor Proteins, Signal Transducing; Alzheimer Disease; Amyloid beta-Peptides; Animals; Dementia; Denmark; Disease Models, Animal; Gene Knock-In Techniques; Genetic Carrier Screening; Humans; Male; Membrane Proteins; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutant Chimeric Proteins; Mutation; Peptide Fragments

Preanalytical sample handling and storage procedures play an extremely important role in reliably measuring neurochemical dementia diagnostics (NDD) biomarkers: Aβ(1-40), Aβ(1-42), Tau, and pTau181. To test different handling and storage conditions, the following protocols were applied: (a) storage at room temperature for one week, (b) deep-freezing and thawing up to three cycles, (c) deep-freezing, thawing and keeping under +4°C for two days before the analysis, and (d) long-term stability of a deeply frozen sample. Between the first and the seventh day of the storage at room temperature, the percentage of the concentrations (compared to the starting concentrations) fluctuated: 104.3-105.3, 97.6-93.2, 100.6-96.8, and 97.9-90.2 for Aβ(1-40), Aβ(1-42), Tau, and pTau181, respectively. Re-freezing cycles resulted in the percentage fluctuations of the concentrations: 101.1-105.5, 95.4-99.7, 98.3-100.0, and 100.5-101.4 for Aβ(1-40), Aβ(1-42), Tau, and pTau181, respectively. Keeping previously frozen/thawed samples under +4°C for two days resulted in the percentage differences of the concentrations: +15.9, +2.2, -1.1, and -0.1 for Aβ(1-40), Aβ(1-42), Tau, and pTau181, respectively. During long-term stability, the coefficients of linear correlation (R(2)) were: Aβ(1-40), 0.007; Aβ(1-42), 0.02; Tau, 0.011; and pTau181, 0.02, and the corresponding inter-assay coefficients of variation: 13.9%, 13.9%, 11.0%, and 10.7% for Aβ(1-40), Aβ(1-42), Tau, and pTau181, respectively. We conclude that the NDD biomarkers are relatively stable when the cerebrospinal fluid sample is kept at room temperature for about four days; one or two thawing/refreezing cycles do not profoundly affect the biomarkers concentrations, however three cycles result in increased unsystematic variation. The four biomarkers seem to be stable in a sample stored deeply frozen for more than two years.

Topics: Amyloid beta-Peptides; Biomarkers; Dementia; Feasibility Studies; Freezing; Humans; Peptide Fragments; Quality Control; Specimen Handling; tau Proteins; Temperature

To investigate the relation of plasma levels of Abeta peptides (Abeta1-40 and Abeta1-42) and apolipoprotein E (APOE) genotype to dementia status, and the duration of Alzheimer's disease (AD) in adults with Down syndrome (DS).. Adults with DS were recruited from community settings and followed up for a mean period of 6.7 years. Plasma levels Abeta1-40 and Abeta1-42 and APOE genotype were determined at the last visit.. There were 83 nondemented participants and 44 participants with prevalent AD. Overall, plasma levels of Abeta1-42, Abeta1-40 and the ratio Abeta1-42/Abeta1-40 did not differ significantly between the adults with DS. Among demented participants, the mean level of Abeta1-40 was significantly lower (157.0 vs. 195.3) and the ratio of Abeta1-42/Abeta1-40 was significantly higher (0.28 vs. 0.16) in those with more than 4 years duration of dementia than in those with 4 or fewer years' duration of dementia. This pattern was generally similar in those with and without an APOE epsilon4 allele.. There is an association between plasma Abeta peptide levels and the duration of AD in older persons with DS. The predictive and diagnostic roles of Abeta1-42 and Abeta1-40 measurements for AD, however, remain controversial. Change in Abeta peptide levels with onset of AD and with the duration of dementia may account for a lack of difference between prevalent cases and nondemented individuals and for variation in the predictive power of Abeta peptide levels.

Topics: Adult; Aged; Alleles; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Cohort Studies; Dementia; Down Syndrome; Female; Genotype; Humans; Male; Middle Aged; Peptide Fragments; Polymorphism, Single Nucleotide; Predictive Value of Tests; Time Factors

We measured concentrations of Abeta peptides 1-42 and 1-40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3-3.8% for Abeta1-42, and 1.8-4.1% for Abeta1-40, inter-assay imprecision for Abeta1-42, Abeta1-40, and Abeta1-42/Abeta1-40 concentration ratio in the range of 2.3-11.5%, 2.2-10.4% and 4.2-9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n=193) had significantly lower Abeta1-42 plasma concentrations (p<0.007), and Abeta1-42/1-40 ratios (p<0.003) compared to patients with other dementias and MCI of other types (n=64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Dementia; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoassay; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests

Amyloid beta(40) (Abeta(40)) is the most abundant Abeta peptide in the brain. The cerebrospinal fluid (CSF) level of Abeta(40) might therefore be considered to most closely reflect the total Abeta load in the brain. Both in Alzheimer's disease (AD) and in normal aging the Abeta load in the brain has a large inter-individual variability. Relating Abeta(42) to Abeta(40) levels might consequently provide a more valid measure for reflecting the change in Abeta metabolism in dementia patients than the CSF Abeta(42) concentrations alone. This measure may also improve differential diagnosis between AD and other dementia syndromes, such as vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).. To investigate the diagnostic value of the CSF Abeta(42)/Abeta(40) ratio in differentiating AD from controls, VaD, DLB and FTD.. We analysed the CSF Abeta(42)/Abeta(40) ratio, phosphorylated tau(181) and total tau in 69 patients with AD, 26 patients with VaD, 16 patients with DLB, 27 patients with FTD, and 47 controls.. Mean Abeta(40) levels were 2850 pg/ml in VaD and 2830 pg/ml in DLB patients, both significantly lower than in AD patients (3698 pg/ml; p<0.01). Abeta(40) levels in AD patients were not significantly different from those in controls (4035 pg/ml; p=0.384). The Abeta(42)/Abeta(40) ratio was significantly lower in AD patients than in all other groups (p <0.001, ANCOVA). Differentiating AD from VaD, DLB and non-AD dementia improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) concentrations alone (p<0.01) The Abeta(42)/Abeta(40) ratio performed equally well as the combination of Abeta(42), phosphorylated tau(181) and total tau in differentiating AD from FTD and non-AD dementia. The diagnostic performance of the latter combination was not improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) alone.. The CSF Abeta42/Abeta40 ratio improves differentiation of AD patients from VaD, DLB and non-AD dementia patients, when compared to Abeta42 alone, and is a more easily interpretable alternative to the combination of Abeta42, p-tau and t-tau when differentiating AD from either FTD or non-AD dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Dementia; Dementia, Vascular; Diagnosis, Differential; Female; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Middle Aged; Peptide Fragments

Increasing evidence is implicating mitochondrial dysfunction as a central factor in the etiology of Alzheimer's disease (AD). The most significant risk factor in AD is advanced age and an important neuropathological correlate of AD is the deposition of amyloid-beta peptide (Abeta40 and Abeta42) in the brain. An AD-like dementia is also common in older individuals with Down syndrome (DS), though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) control region (CR) mutations accumulate with age in post-mitotic tissues including the brain and that the level of mtDNA mutations is markedly elevated in the brains of AD patients. The elevated mtDNA CR mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. We now show that mtDNA CR mutations increase with age in control brains; that they are markedly elevated in the brains of AD and DS and dementia (DSAD) patients; and that the increased mtDNA CR mutation rate in DSAD brains is associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD and DSAD patients, and distinctive somatic mtDNA mutations, often at high heteroplasmy levels, are seen in AD and DSAD brain and blood cells DNA. In aging, DS, and DSAD, the mtDNA mutation level is positively correlated with beta-secretase activity and mtDNA copy number is inversely correlated with insoluble Abeta40 and Abeta42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Child; Child, Preschool; Dementia; DNA, Mitochondrial; Down Syndrome; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mitochondrial Diseases; Peptide Fragments; Young Adult

Amyloid-beta(Abeta) aggregation is a major hallmark of Alzheimer's disease (AD). Previous studies have suggested that only unbound Abeta can take part in the aggregation process. Therefore, endogenous Abeta-binding proteins may have an important role in preventing AD. Here, we analyzed cerebrospinal fluid (CSF) samples from 35 subjects with AD, 18 subjects with frontotemporal dementia (FTD) and 29 non-demented controls to test if reduced Abeta-binding capacity in CSF is a specific feature of AD. A panel of known Abeta-binding CSF proteins, including beta-trace/prostaglandin D2 synthase (beta-trace), transthyretin (TTR), cystatin C (CysC) and alpha(1)-antitrypsin (AAT), were quantified and related to diagnosis and CSF levels of Abeta(1-38), Abeta(1-40) and Abeta(1-42). AD patients displayed a mild reduction in the CSF levels of beta-trace (p=0.020), CysC (p=0.017), AAT (p=0.019) and TTR (p=0.012) compared with controls. While the reductions in AAT and TTR were AD-specific, the levels of beta-trace and CysC were also reduced in FTD. As expected, CSF Abeta(1-42) was reduced in AD compared with controls (p=0.00005) and with FTD patients (p=0.015). Positive correlations between Abeta(1-42) and beta-trace, CysC and TTR, respectively, were seen only in the AD group, suggesting that deficient Abeta-binding capacity in CSF may contribute to the amyloidogenic process in AD.

Topics: Aged; Aged, 80 and over; alpha 1-Antitrypsin; Alzheimer Disease; Amyloid beta-Peptides; Cystatin C; Dementia; Electrochemistry; Female; Humans; Intramolecular Oxidoreductases; Linear Models; Lipocalins; Male; Nephelometry and Turbidimetry; Peptide Fragments; Prealbumin; Statistics, Nonparametric

To explore mechanisms through which altered peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1alpha expression in neurons might be developed as a novel therapeutic strategy in AD.. Case-control. Patients Human postmortem brain (hippocampal formation) samples from AD cases and age-matched non-AD cases.. Using genome-wide complementary DNA microarray analysis, we found that PGC-1alpha messenger RNA expression was significantly decreased as a function of progression of clinical dementia in the AD brain. Following confirmatory real-time polymerase chain reaction assay, we continued to explore the role of PGC-1alpha in clinical dementia and found that PGC-1alpha protein content was negatively associated with both AD-type neuritic plaque pathology and beta-amyloid (Abeta)(X-42) contents. Moreover, we found that the predicted elevation of amyloidogenic Abeta(1-42) and Abeta(1-40) peptide accumulation in embryonic cortico-hippocampal neurons derived from Tg2576 AD mice under hyperglycemic conditions (glucose level, 182-273 mg/dL) coincided with a dose-dependent attenuation in PGC-1alpha expression. Most importantly, we found that the reconstitution of exogenous PGC-1alpha expression in Tg2576 neurons attenuated the hyperglycemic-mediated beta-amyloidogenesis through mechanisms involving the promotion of the "nonamyloidogenic" alpha-secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression.. Therapeutic preservation of neuronal PGC-1alpha expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Abeta peptides.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Case-Control Studies; Cells, Cultured; Culture Media, Conditioned; Dementia; Disease Progression; Dose-Response Relationship, Drug; Down-Regulation; Embryo, Mammalian; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Profiling; Glucose; Green Fluorescent Proteins; Heat-Shock Proteins; Hippocampus; Humans; Mice; Mice, Transgenic; Neurons; Oligonucleotide Array Sequence Analysis; Peptide Fragments; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; RNA, Messenger; Transcription Factors; Transfection

beta-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673-->valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid (Abeta) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Abeta aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.

Topics: Adult; Alzheimer Disease; Amino Acid Substitution; Amyloid; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Cell Line; Dementia; Female; Genes, Recessive; Heterozygote; Homozygote; Humans; Kinetics; Male; Mutation; Pedigree; Peptide Fragments; Protein Binding; Transfection

Topics: Aged; Amyloid beta-Peptides; Biomarkers; Chromatography, High Pressure Liquid; Creatinine; Dementia; Enzyme-Linked Immunosorbent Assay; Female; Folic Acid; Germany; Homocysteine; Humans; Immunoassay; Linear Models; Male; Middle Aged; Nephelometry and Turbidimetry; Nerve Degeneration; Peptide Fragments; tau Proteins; Vitamin B 12

Truncated forms and full-length forms of the amyloid-beta 40 (Abeta40) are key molecules in the pathogenesis of dementia, and are detectable in CSF. Reliable methods to detect these biomarkers in CSF are of great importance for understanding the disease mechanisms and for diagnostic purposes.. VU-alpha-Abeta40, a monoclonal antibody (mAb) specifically detecting Abeta40, was generated and characterized by solid and fluid phase ELISA, surface plasmon resonance spectroscopy (SPRS), immunoprecipitation (IP), immunohistochemical and Western blot (WB) analysis. In addition, an ELISA with VU-alpha-Abeta40 as catching and 6E10 as detecting mAbs was set up and validated. This ELISA was used to measure Abeta40 in CSF of controls (N=27), patients with Alzheimer's disease (AD; N=20), frontotemporal lobe dementia (FTLD; N=14), noninflammatory (N=15) and inflammatory (N=15) neurological conditions.. VU-alpha-Abeta40 specifically recognizes Abeta40 with high affinity (K(A)=1.3x10(9) M(-1)) and detects Abeta40 in AD brain specimens. The developed sandwich ELISA has a detection limit of 0.21 ng/mL, a mean recovery of 90%, and an intra- and inter-assay CV of 1.4% and 7.3%. FTLD patients had a lower mean level of Abeta40 (8.8 (1.9) ng/mL) than controls (12.0 (1.7) ng/mL); p<0.01).. VU-alpha-Abeta40 was successfully implemented in an ELISA which enables us to measure Abeta40 accurately in human CSF. Clinical validation revealed lower levels of Abeta40 in FTLD patients. This finding opens new possibilities for early and differential diagnosis of dementia.

Topics: Aged; Amyloid beta-Peptides; Antibodies, Monoclonal; Biomarkers; Dementia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Peptide Fragments

The definite diagnosis of Alzheimer's disease (AD) is based on post mortem pathological examination. To date, there is no laboratory test that can discriminate AD patients from healthy individuals. In the perspective of recent knowledge, there are three cerebrospinal fluid (CSF) markers which have the highest sensitivity and specificity: A beta(1-40), A beta(1-42), and p-tau. In the present study, 15 'Probable Alzheimer's Disease' (PAD) patients and 15 control subjects were included. PAD patients were selected from the patients of Dokuz Eylül University Neurology Department Dementia outpatient clinic and control subjects were selected from the patients who were undergone epidural anesthesia because of any surgical operation. The concentrations of Ab1-40, Ab1-42, and p-tau in CSF were quantified by using ELISA. Also, the effects of 'PAD patients' CSF on the survival of PC12 cell line were assessed. There was a significant decrease of Ab1-40 and increase of p-tau in patients with AD when compared with controls. Ab1-42 concentration was not significantly different between groups. There was a positive correlation between duration of the disease and CSF of p-tau concentration in patients with AD. There was no significant difference in cell line viability values between groups.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Biomarkers; Cell Survival; Chi-Square Distribution; Cytotoxins; Dementia; Female; Humans; Male; Middle Aged; PC12 Cells; Peptide Fragments; Rats; ROC Curve; Statistics, Nonparametric; tau Proteins

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders with heterogeneous clinical presentation but common neuropathological characteristics and pathophysiological substrates, which led to the view of ALS and FTLD representing two manifestations of a clinicopathological spectrum. For both diseases, changes in metabolism of beta-amyloid precursor protein (APP) are reported. In a pilot study, we analyzed cerebrospinal fluid from patients of the ALS-FTLD spectrum for APP processing products. ALS patients show elevated absolute levels of soluble APP and a shift towards the nonamyloidogenic APP processing pathway in contrast to patients with FTLD or ALS + FTLD. Changes in Abeta pattern could be described, allowing separation of patients with pure FTLD from ALS + FTLD. Combination of sAPP and Abeta values improves group differentiation. These findings may provide information on pathophysiological processes in the ALS-FTLD disease spectrum and could have impact in neurochemical diagnosis. We propose to expand this study to larger patient groups comprising followed up cases with known neuropathology.

Topics: Aged; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; Area Under Curve; Dementia; Female; Humans; Male; Middle Aged; Peptide Fragments; ROC Curve

We carried out a quantitative analysis of transthyretin (TTR), total tau protein and amyloid-beta (Abeta) peptide (1-40 and 1-42) in the lumbar cerebrospinal fluid of 106 patients with different forms of dementia including Alzheimer's disease (AD), Creutzfeldt-Jakob-disease (CJD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and normal pressure hydrocephalus (NPH) in comparison to healthy controls. Our study revealed that Abeta_{1-42} levels were decreased in all patients irrespective of dementia type. Tau protein levels were abnormal in all degenerative dementia except of NPH. Tau levels did not allow differential diagnosis of dementia type except for CJD, where we observed extremely high CSF levels. In other dementia types, levels were elevated in a similar range. Transthyretin levels were selectively decreased in AD and NPH, thus revealing the potential of this protein to be used as additional biomarker in the neurochemical differential diagnosis of AD. A significant negative correlation of TTR CSF levels and disease severity in AD was observed.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Creutzfeldt-Jakob Syndrome; Dementia; Diagnosis, Differential; Female; Humans; Hydrocephalus, Normal Pressure; Lewy Body Disease; Male; Mental Status Schedule; Middle Aged; Peptide Fragments; Prealbumin; Reference Values; Statistics as Topic; tau Proteins

The risk for dementia in Alzheimer's disease (DAD) in adults with Down syndrome (DS) is higher than in the general adult population. Hypercholesterolaemia has been reported as a risk factor for DAD in the general population. This study investigated the role of serum cholesterol levels in the onset of DAD in the DS population.. This study investigated total serum cholesterol levels in 179 DS persons (with and without DAD). The possible association between Apolipoprotein E and amyloid beta1-40 and beta1-42 levels was also investigated.. No statistically significant association was found between total serum cholesterol levels and dementia in AD or with amyloid beta levels. However for DS adults with an apoE epsilon4 allele significantly higher serum cholesterol levels were found.. Hypercholesterolaemia is not a risk factor for DAD in persons with DS. However, DS persons with an apoE epsilon4 allele are susceptible to high serum cholesterol. Such individuals should be screened on a regular basis.

Topics: Adolescent; Adult; Alleles; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Biomarkers; Cholesterol; Dementia; Down Syndrome; Female; Gene Frequency; Humans; Male; Middle Aged; Peptide Fragments; Young Adult

The role of amyloid metabolism in the pathophysiology of frontotemporal lobar degeneration (FTLD) has yet to be elucidated. We compared CSF levels of amyloid beta 1-40 (Abeta40) and amyloid beta 1-42 (Abeta42) in patients with FTLD (n = 21) versus patients with Alzheimer's disease (AD, n = 39) and in control subjects (n = 30). While in AD cases Abeta42 levels were lower and CSF Abeta40 levels equal to those in controls, a significant decrease in Abeta40 and increase in the CSF Abeta42/Abeta40 ratio was observed in FTLD compared with AD and control subjects. These findings favour a differential involvement of amyloid beta peptides in FTLD compared with AD.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Case-Control Studies; Dementia; Female; Humans; Male; Middle Aged; Peptide Fragments

Two hereditary forms of cerebrovascular amyloidosis, familial British and Danish dementias (FBD and FDD), share striking similarities with Alzheimer's disease (AD) despite structural differences among their amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD). Neuropathological lesions in these disorders include neurofibrillary tangles, parenchymal amyloid and pre-amyloid deposits and overwhelming cerebral amyloid angiopathy co-localizing with reactive microglia and multiple amyloid associated proteins including activation products of the complement cascade. Immunohistochemical analysis of FBD and FDD brain lesions unveiled the presence of serum amyloid P-component (SAP) primarily associated with thioflavin positive amyloid deposits in spite of the significant pre-amyloid burden existing in both disorders. Using affinity chromatography and ELISA binding assays we demonstrated specific, calcium-dependent, saturable, high affinity binding interactions between SAP and ABri/ADan peptides, with dissociation constant values in the sub-nanomolar range and within the same order of magnitude as those resulting from the interaction of SAP with Alzheimer's Abeta1-40 and Abeta1-42. The preferential association of SAP with fibrillar amyloid lesions and not with non-fibrillar pre-amyloid deposits is puzzling, suggesting that SAP modulates the assembly and stability of the final fibril rather than participating in the early steps of protein misfolding and oligomerization.

Topics: Adaptor Proteins, Signal Transducing; Aged; Amyloid; Amyloid beta-Peptides; Benzothiazoles; Biomarkers; Brain; Cerebral Amyloid Angiopathy, Familial; Dementia; Denmark; England; Humans; Immunohistochemistry; Membrane Glycoproteins; Membrane Proteins; Neurofibrils; Peptide Fragments; Plaque, Amyloid; Protein Subunits; Serum Amyloid P-Component; Thiazoles

In the past years, the possible involvement of inflammation in the pathogenesis of dementia has been the subject of several investigations. However there are restricted data about the profile of the inflammatory and soluble proteins in well evaluated Alzheimer's disease (AD), vascular dementia (VD), mild cognitive impairment (MCI) and healthy controls. There are also no reliable data regarding the relationship between the overlapping protein levels and cognitive or functional decline. We measured levels of IL-1beta, IL-2, IL-6, IL-18, TNF-alpha, beta-Amlyloid 1-40 and alpha1-antichymotrypsin levels in plasma in groups of total 82 subjects with AD, MCI, VD and controls using enzyme-linked immunosorbent assay (ELISA) method. Our study samples showed high levels of proinflammatory cytokine levels (especially IL-18) in all patient groups but only high levels of alpha1-antichymotrypsine in VD patients compared to controls. There is no significant correlation between the laboratory and clinical variables except for a link between IL-1beta and NPI scores of AD. In conclusion, this study yielded evidence of some shared mechanisms underlying AD and VD and thus motivates further studies of inflammatory markers in various types of dementia and MCI.

Topics: Acute-Phase Proteins; Aged; Amyloid beta-Peptides; Analysis of Variance; Biomarkers; Case-Control Studies; Cognition Disorders; Cross-Sectional Studies; Dementia; Diagnosis, Differential; Female; Humans; Interleukins; Male; Matched-Pair Analysis; Middle Aged; Peptide Fragments; Reference Values; Severity of Illness Index; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

The intra vitam diagnosis of different dementias is still based on clinical grounds. So far, no technical investigations have been available to support these diagnoses. For tau protein and beta-amyloid(1-42) in cerebrospinal fluid (CSF), promising results for the diagnosis of Alzheimer's disease (AD) have been reported; however, their differential diagnostic spectrum is limited, as was recently shown for dementia with Lewy bodies (DLB) and for AD. Therefore, further marker proteins have to be established to ameliorate, support, and differentiate these clinical diagnoses. We evaluated beta-amyloid(1-40) and phosphorylated tau protein (181p), in addition to total tau protein and beta-amyloid(1-42), in 20 patients with DLB, 34 AD patients, and 20 non-demented neurological controls (NDCs). All markers could differentiate between the dementia groups (AD, DLB) and the controls. AD and DLB could be differentiated only by levels of total tau protein and by the ratio total tau protein/phosphorylated tau protein. However, values still overlapped markedly. In some cases, tau protein levels in CSF may contribute to the clinical distinction between DLB and AD, but the value of the markers is still limited, especially because of mixed pathology. We conclude that more specific markers have to be established to differentiate between these diseases.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Dementia; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Peptide Fragments; Phosphorylation; tau Proteins

Amyloid beta peptides (Abeta) are important components of plaques in Alzheimer's disease. Plasma concentrations of Abeta(1-40) and Abeta(1-42) rise with age and are increased in people with mutations that cause early-onset Alzheimer's disease. However, Abeta(1-42) concentrations may decrease early in the dementia process. We postulated that concentrations of Abeta(1-40) and Abeta(1-42) in plasma are associated with risk of dementia.. We did a case-cohort study embedded in the prospective, population-based Rotterdam Study. Of 6713 participants at risk for dementia, a random sample of 1756 people was drawn. During follow-up (mean 8.6 years), 392 incident dementia cases were identified. We investigated the association between plasma Abeta concentrations and risk of dementia and its subtypes using Cox proportional hazard models.. High concentrations of Abeta(1-40) but not Abeta(1-42) at baseline were associated with an increased risk of dementia. Compared with the first quartile of Abeta(1-40), age and sex-adjusted hazard ratios for dementia for the second, third, and fourth quartiles were 1.07 (95% CI 0.72-1.58), 1.16 (0.78-1.70), and 1.46 (1.01-2.12). People with an increased Abeta(1-42)/Abeta(1-40) ratio had a reduced risk of dementia. Compared with the first quartile of the Abeta(1-42)/Abeta(1-40) ratio, hazard ratios for the second, third, and fourth quartiles were 0.74 (0.53-1.02), 0.62 (0.44-0.88), and 0.47 (0.33-0.67). Associations were similar for Alzheimer's disease and vascular dementia.. High plasma concentrations of Abeta(1-40), especially when combined with low concentrations of Abeta(1-42), indicate an increased risk of dementia. A potential role of plasma Abeta concentrations as a marker of incipient dementia warrants further investigation.

Topics: Aged; Amyloid beta-Peptides; Cohort Studies; Confidence Intervals; Dementia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Proportional Hazards Models; Risk; Time Factors

Although evidence suggests that extensive cortical beta-amyloid (Abeta) deposition is essential in Alzheimer disease (AD), it is also detected in nondemented elderly individuals with pathologic aging (PA). Given evidence that neutral endopeptidase (NEP) or neprilysin, a key enzyme for clearance of Abeta, is decreased in AD, the goal of the present study was to determine if NEP was also decreased in PA. We measured NEP immunoreactivity in frontal cortex of 12 AD and six PA cases and compared this with 10 normal (N) elderly individuals. None had any significant other pathology, and they were similar with respect to age, sex, and postmortem delay. In addition, Abeta1-40 and Abeta1-42 were measured by enzyme-linked immunosorbent assay (ELISA), whereas tau, synaptophysin, and alpha-synuclein were measured on Western blots. The AD cases had more neuritic plaques, neurofibrillary tangles, higher Braak stage, and more tau immunoreactivity in frontal cortex than both PA and N. In contrast, both PA and AD had more senile plaques and Abeta1-42 than N. NEP immunoreactivity was decreased in AD but not in PA. The decrease was unlikely the result of neuronal or synaptic loss because NEP immunoreactivity in frontotemporal degeneration with comparable degrees of synaptic loss as the AD cases was not different from control subjects. Although NEP enzyme activity was decreased in approximately half the AD cases, on average, it was not decreased compared with N or PA. The results add further evidence that PA is distinct from AD and indicate that decreased Abeta degradation by NEP is unlikely to contribute significantly to amyloid deposition in PA or, in many cases, of AD.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Blotting, Western; Case-Control Studies; Dementia; Enzyme-Linked Immunosorbent Assay; Female; Frontal Lobe; Humans; Male; Neprilysin; Neurofibrillary Tangles; Peptide Fragments; Plaque, Amyloid; Postmortem Changes; Statistics, Nonparametric; tau Proteins

Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and beta-amyloid (Abeta)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with Abeta-(1-42) and Abeta-(4-42) in approximately 1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas Abeta was mainly Abeta-(4-42). In all cases, the presence of Abeta-(X-40) was negligible, a surprising finding in view of the prevalence of Abeta40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and Abeta molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neuro fibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.

Topics: Adult; Alzheimer Disease; Amyloid beta-Peptides; Blood Vessels; Dementia; Denmark; Humans; Immunoblotting; Immunoenzyme Techniques; Male; Peptide Fragments; Plaque, Amyloid

The pathophysiological basis of cognitive dysfunction, including frontotemporal dementia (FTD), in patients with amyotrophic lateral sclerosis (ALS) and ALS with dementia (ALSD) remains unclear. On the other hand, increased expression of cyclooxygenase-2 (COX-2) in the spinal cord is thought to play a pivotal role in motor neuron degeneration in ALS. In this study, to assess the relationship between the neuronal COX-2 expression in the cerebrum, the formation of tau- and alpha-synuclein-negative but ubiquitin-positive neuronal inclusions (UPIs), and dementia in motor neuron disease (MND), we examined neuronal COX-2 immunoreactivity in the frontal cortex and hippocampus of patients with non-demented ALS without UPIs ( n=11), ALSD with UPIs ( n=6), and normal controls ( n=24) using a quantitative immunohistochemical technique. Neuronal COX-2 expression in all CA1-4 in the hippocampus was significantly up-regulated in the ALSD group, and, to lesser degree but significantly, in the ALS group. Neuronal COX-2 expression in the frontal cortex was also significantly up-regulated in the ALSD group but not in the ALS group. These findings suggest that (1) the frontal cortex and hippocampus of MND are involved in the same pathogenic process associated with COX-2 induction that has been observed in spinal anterior horn cells, (2) COX-2 induction in the cerebrum is a pathogenic process that can occur even in the absence of UPI formation in MND, and (3) COX-2 expression in the cerebrum may be associated with cognitive dysfunction in MND.

Topics: Aged; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Cell Count; Cyclooxygenase 2; Dementia; Female; Frontal Lobe; Gene Expression Regulation; Hippocampus; Humans; Immunohistochemistry; Isoenzymes; Male; Membrane Proteins; Middle Aged; Peptide Fragments; Postmortem Changes; Prostaglandin-Endoperoxide Synthases; Ubiquitin; Up-Regulation

Topics: Adult; Amino Acid Substitution; Amyloid beta-Peptides; Apolipoproteins E; Cells, Cultured; Culture Media, Conditioned; Dementia; Disease Progression; DNA Mutational Analysis; Female; Fibroblasts; Humans; Male; Membrane Proteins; Mental Recall; Middle Aged; Neuropsychological Tests; Paraparesis, Spastic; Peptide Fragments; Phenotype; Point Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Presenilin-1

Deposition of beta-amyloid (Abeta) is an early pathogenic event in Alzheimer's disease (AD). We measured Abeta42 and Abeta40 in cerebrospinal fluid (CSF) in a population-based sample of 85-year-olds, 27 demented and 35 non-demented. During the following 3 years, 7 of the 35 non-demented individuals had developed dementia, while 28 remained non-demented. Reduced CSF levels of both Abeta42 (p = 0.001) and Abeta40 (p = 0.0001) were found in patients with manifest AD and vascular dementia at the age of 85. Non-demented individuals who developed dementia during follow-up had lower levels of CSF- Abeta42 (p = 0.003), but not CSF-Abeta40 (p = 0.96), than those who remained non-demented. The odds ratio for development of dementia was 8.2 (p = 0.027) for individuals in the lower 50th percentile of CSF-Abeta42, while none of those in the highest 33rd percentile of CSF-Abeta42 developed dementia during follow-up. There were no significant differences between carriers and non-carriers of the apolipoprotein E epsilon4 allele regarding CSF-Abeta42 or CSF-Abeta40. Our study suggests that low CSF-Abeta42 is found also in an unselected population-based sample of old demented patients and provides the first evidence of a disturbance in the metabolism of Abeta, specifically involving Abeta42, before the onset of clinical symptoms in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Brain; Dementia; Female; Follow-Up Studies; Humans; Male; Peptide Fragments; Population Surveillance; Protein Isoforms; Risk Factors; Sampling Studies

In a group of 28 older men with either subjective memory loss or dementia, serum total testosterone and sex hormone binding globulin (SHBG) correlated inversely with plasma levels of amyloid beta peptide 40 (Abeta40, r=-0.5, P=0.01 and r=-0.4, P=0.04, respectively). Calculated free testosterone was also inversely correlated (r=-0.4, P=0.03), and all three relationships remained statistically significant after allowing for age. A similar but non-significant trend was seen with dehydroepiandrosterone sulphate (DHEAS), and neither luteinising hormone (LH) nor estradiol correlated with Abeta40. These data demonstrate that lower androgen levels are associated with increased plasma Abeta40 in older men with memory loss or dementia, suggesting that subclinical androgen deficiency enhances the expression of Alzheimer's disease-related peptides in vivo. An inverse correlation exists between SHBG and Abeta40, warranting further investigation.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Androgens; Dementia; Humans; Male; Middle Aged; Peptide Fragments; Risk Factors; Sex Hormone-Binding Globulin; Testosterone

Establishing the diagnosis in patients with clinical signs and symptoms suggesting primary degenerative disease with marked frontal lobe involvement is difficult. Neuroimaging methods, in particular positron emission tomography (PET) with the tracer 18fluoro-2-deoxyglucose (FDG) and cerebrospinal fluid (CSF) examination of beta-amyloid and tau-protein levels may give additional information. We report five patients with clinical and radiological features of degenerative dementia with predominantly frontal involvement and one patient with primary progressive aphasia Diagnostic work-up included computed tomography (CT), magnetic resonance imaging (MRI), PET and tau-protein and beta-amyloid level determination in CSF. While neuropsychological performance varied among patients, CT and MRI demonstrated persistently frontal lobe involvement. PET revealed corresponding changes with frontal hypometabolism, but in addition, four patients (among them two with no corresponding temporal changes in CT or MRI) showed a decreased glucose uptake in the temporal cortices. CSF samples from five patients revealed elevated beta-amyloid 1-42 and tau levels in three and two patients, respectively. Reduced beta-amyloid 1-40 was found in two patients. We conclude that occurrence of clinical symptoms of frontotemporal dementia is accompanied by frontal hypometabolism regardless of additional clinical findings. The value of determination of beta-amyloid and tau protein levels remains to be determined.

Topics: Aged; Amyloid beta-Peptides; Cerebrospinal Fluid Proteins; Dementia; Female; Frontal Lobe; Humans; Individuality; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; Psychiatric Status Rating Scales; tau Proteins; Temporal Lobe; Tomography, Emission-Computed; Tomography, X-Ray Computed

Cerebrospinal fluid samples from a total of 157 subjects consisting of 55 patients with sporadic Alzheimer's disease (AD), 34 normal controls, 23 patients with non-AD dementia, and 45 with other neurological diseases were examined by ELISA of tau, A beta 1-40, and A beta 1-42(43). The AD group had a significantly higher level of tau than the normal control group (P < 0.001), and the diagnostic sensitivity was 31% and specificity was 94%. CSF A beta 1-40 levels did not show any significant differences. Although the level of A beta 1-42(43) was decreased significantly in the AD group compared to the control group (P < 0.005), the overlap of A beta 1-42(43) levels among all groups meant that none of the AD samples exceeded the cut-off value, the mean 2SD of normal control subjects. Reduction of A beta 1-42(43) levels in AD resulted in a significant increase in the ratio of A beta 1-40 to A beta 1-42(43) (A beta ratio) as an improved marker. The diagnostic sensitivity and specificity of A beta ratio were 51% and 82% respectively. The three indexes, using the tau level and A beta ratio (tau or A beta ratio, deviation score and tau x A beta ratio), showed better sensitivity (58%, 67%, 69%) and specificity (82%, 86%, 88%) than previously reported methods. Combination assay for CSF tau, A beta 1-40 and A beta 1-42(43) in CSF is a biological marker of AD and may be useful to biochemically monitor subjects under treatment.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Dementia; Female; Humans; Male; Middle Aged; Nervous System Diseases; Peptide Fragments; Reference Values; tau Proteins

To supplement the existing pharmacological evidence describing the effects of nimodipine, a 1,4-dihydropyridine with calcium channel blocking properties, our group has used a multidisciplinary approach. This work attempts to characterize the mechanism of action of nimodipine in neurons as well as investigate the effects of nimodipine in models of neurodegeneration and dementia. Patch voltage clamp studies demonstrated high-affinity nimodipine block of voltage-dependent L-type calcium channel activity in central neurons from primary cultures of neonatal rat hippocampus. Nimodipine potently blocks depolarization-induced increases in free calcium throughout the soma of these hippocampal neurons. In addition, somatic free calcium elevations induced by acute beta A4(25-35) exposure are also potently blocked by nimodipine. In behavioral studies, nimodipine produced enhanced retention in aging rabbits on eyeblink conditioning and also was shown to protect against medial septal lesion-induced retention deficits in a spatial learning task. These findings, from channel to behavioral effects, support the therapeutic usefulness of nimodipine in the treatment of aging and dementia and are consistent with the view that calcium regulation is important in disorders of neuronal degeneration.

Topics: Aging; Amyloid beta-Peptides; Animals; Behavior, Animal; Calcium; Cells, Cultured; Dementia; Female; In Vitro Techniques; Male; Nerve Degeneration; Neurons; Nimodipine; Peptide Fragments; Rabbits; Rats; Retention, Psychology