amyloid-beta-peptides and Cognitive-Dysfunction

An amyloid-β (Aβ) positron emission tomography (Aβ-PET) scan of the human brain could lead to an early diagnosis of Alzheimer's disease (AD) and estimate disease progression. However, Aβ-PET imaging is expensive, invasive, and rarely applicable to cognitively normal subjects at risk for dementia. The identification of blood biomarkers predictive of Aβ brain deposition could help the identification of subjects at risk for dementia and could be helpful for the prognosis of AD progression.. This study aimed to analyze the prognostic accuracy of blood biomarkers in predicting Aβ-PET status along with progression toward AD.. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched bibliographic databases from 2010 to 2020. The quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool.. A total of 8 studies were retrieved. The prognostic accuracy of Aβ-PET status was calculated by obtaining ROCs for the following biomarkers: free, total, and bound Aβ42 and Aβ40; Aβ42/40 ratio; neurofilaments (NFL); total tau (T-tau); and phosphorylated-tau181 (P-tau181). Higher and lower plasma baseline levels of P-tau181 and the Aβ42/40 ratio, respectively, showed consistently good prognostication of Aβ-PET brain accumulation. Only P-tau181 was shown to predict AD progression.. In conclusion, the Aβ42/40 ratio and plasma P-tau181 were shown to predict Aβ-PET status. Plasma P-tau181 could also be a preclinical biomarker for AD progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Cognitive Dysfunction; Disease Progression; Humans; Peptide Fragments; Phosphorylation; Positron-Emission Tomography; Prodromal Symptoms; tau Proteins

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

Easily accessible biomarkers for Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and related neurodegenerative disorders are urgently needed in an aging society to assist early-stage diagnoses. In this study, we aimed to develop machine learning algorithms using the multiplex blood-based biomarkers to identify patients with different neurodegenerative diseases. Plasma samples (

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Female; Humans; Machine Learning; Male; Middle Aged; Neurodegenerative Diseases; Peptide Fragments; tau Proteins

Plasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce.. To investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns.. This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020.. Plasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study.. Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed.. A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107.. In this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.

Topics: Aged; Amyloid beta-Peptides; Apolipoprotein E4; Cognition; Cognitive Dysfunction; Correlation of Data; Diagnostic Self Evaluation; Female; Geriatric Assessment; Humans; Independent Living; Male; Memory Disorders; Peptide Fragments

Varicella-zoster virus (VZV) is one of the most common agents causing viral infections of the central nervous system (CNS). VZV encephalitis is associated with severe neurological sequelae, despite antiviral treatment. Cognitive impairment has been reported and VZV has been associated with dementia. Our aim was to investigate the cognitive impairment and cerebrospinal fluid biomarkers in a follow-up study of patients with VZV encephalitis. Thirteen patients with VZV encephalitis, diagnosed by detection of VZV DNA in cerebrospinal fluid (CSF) by PCR and concomitant symptoms of encephalitis, were included. Neuropsychological assessment in parallel with a lumbar puncture to obtain CSF was performed 1.5-7 years after acute disease. The CSF biomarkers neurofilament light chain (NFL), S100B, glial fibrillary acidic protein (GFAP), amyloid-β (Aβ) 40 and Aβ42, total tau (t-tau) and phosphorylated tau (p-tau) were analysed and compared to controls (n = 24). Cognitive impairment was shown in the domains of executive functions and speed/attention and to a minor degree in the domains of learning/memory and language, indicated by a significantly poorer performance on seven neuropsychological test variables. No convincing evidence of alterations in concentrations of biomarkers in the CSF were shown. Our results indicate that patients with VZV encephalitis suffer from cognitive impairment long time after acute disease. Importantly, these impairments do not seem to be accompanied by biomarker evidence of ongoing neuronal or astrocytic injury/activation or induction of dementia-related brain pathologies by the infection.

Topics: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; DNA, Viral; Encephalitis, Varicella Zoster; Female; Follow-Up Studies; Glial Fibrillary Acidic Protein; Herpesvirus 3, Human; Humans; Male; Middle Aged; Neurofilament Proteins; Peptide Fragments; Pilot Projects; S100 Calcium Binding Protein beta Subunit; tau Proteins

Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD).. We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months).. Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation.. We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic studies of antiamyloid drugs.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Blood Chemical Analysis; Cognitive Dysfunction; Disease Progression; Donepezil; Female; Heterozygote; Humans; Indans; Longitudinal Studies; Male; Nootropic Agents; Peptide Fragments; Piperidines; Severity of Illness Index; Simvastatin; Vitamin E

To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).. Randomized, double-blind, placebo-controlled trial.. Clinical research unit of a Veterans Affairs medical center.. The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention  Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).. Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.. Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.. These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration  clinicaltrials.gov Identifier: NCT00438568.

Topics: Administration, Intranasal; Aged; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Hospitals, Veterans; Humans; Hypoglycemic Agents; Immunoassay; Insulin; Least-Squares Analysis; Male; Neuropsychological Tests; Peptide Fragments; Pilot Projects; Positron-Emission Tomography; Psychiatric Status Rating Scales; Spinal Puncture; tau Proteins

AD is the most common neurodegenerative disorder characterized by progressive memory impairment and cognitive deficits. The pathology of AD is still unclear; however, several studies have shown that the aggregation of the Aβ peptide in the CNS is an exclusively pathological process involved in AD. Currently, there is no proven medication to cure or prevent the disease progression. Nevertheless, various therapeutic approaches for AD show only relief of symptoms and mostly work on cognitive recovery. However, one of the promising approaches for therapeutic intervention is to use inhibitors for blocking the Aβ peptide aggregation process. Recently, herbal phenolic compounds have been shown to have a therapeutic property for treatment of AD due to their multifaceted action. In this study, we investigated the effectiveness of SA, Gn Rb1, and DMyr on inhibiting the aggregation and toxicity of Aβ40 and Aβ42 using different biochemical and cell-based assays. Our results showed that SA and DMyr inhibit Aβ40 and Aβ42 fibrillation, seeded aggregation, and toxicity. Gn Rb1 did not have any effect on the aggregation or toxicity induced by Aβ40 and Aβ42. Moreover, SA and DMyr were able to disaggregate the preformed fibrils. Overall, these compounds may be used alone or synergistically and could be considered as a lead for designing new compounds that could be used as effective treatment of AD and related disorders.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Humans; 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

Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable.. To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone.. Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging (MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31-513).. Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p = 0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p = 0.04), or lower CSF Aβ40 at presentation (rho = -0.83; p = 0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p = 0.03) or higher late ARIA-E scores (rho = 0.70; p = 0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p = 0.66).. Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Anti-Inflammatory Agents; Biomarkers; Cerebral Amyloid Angiopathy; Cognitive Dysfunction; Critical Care; Electroencephalography; Encephalitis; Female; Humans; Leukocytosis; Longitudinal Studies; Magnetic Resonance Imaging; Male; Methylprednisolone; Neuroimaging; Peptide Fragments; tau Proteins; Treatment Outcome

Imaging with β-amyloid (Aβ) positron emission tomography (PET) has the potential to aid the diagnosis of the cause of cognitive impairment affecting people living with HIV (PLWH) when neurodegenerative disorders are considered. We evaluated the clinical utility of [18F]Florbetaben (FBB) in PLWH with cognitive symptoms.. Imaging with FBB PET was performed in 20 patients with cognitive concerns about dementia. Neuropsychological testing, plasma neurofilament light protein, plasma Aβ40, Aβ42, and cerebrospinal fluid Aβ42, tau, and HIV RNA were obtained. FBB PET images were assessed visually by 3 readers blinded to the clinical diagnosis and quantitatively by obtaining a composite cortical to cerebellar cortex standardized uptake value ratio (SUVR). FBB SUVR from 10 age-matched healthy controls was compared with SUVR of PLWH.. Most participants were men (90%) of white ethnicity (90%) with a median age (interquartile range) of 59 (43-79) years. Median CD4 count was 682 (74-1056). All patients were on combination antiretroviral therapy with plasma and cerebrospinal fluid HIV RNA <40 copies/mL. Fourteen patients had objective cognitive impairment including 2 who met clinical criteria for a diagnosis of dementia. No significant differences in composite SUVRs between PLWH and controls [mean (SD): 1.18 (0.03) vs. 1.16 (0.09); P = 0.37] were observed. Four patients were FBB+ with the highest SUVR in the posterior cingulate, superior temporal, and frontal superior lobe. Amyloid PET results contributed to a change in diagnosis and treatment for 10 patients.. [18F]Florbetaben PET has potential as an adjunctive tool in the diagnosis of PLWH with cognitive impairment, increasing diagnostic certainty and optimizing management.

Topics: Adult; Aged; Amyloid beta-Peptides; Aniline Compounds; Brain; CD4 Lymphocyte Count; Cognitive Dysfunction; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Neurodegenerative Diseases; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; RNA, Viral; Stilbenes; tau Proteins

Evidence of cerebral amyloidosis, by altered levels of the peptide Aß1-42 or the Aß1-42/Aß1-40 ratio, is a necessary condition to accept the presence of Alzheimer's disease (AD), according to the 2018 criteria of the National Institute on Aging and Alzheimer's Association (NIA-AA 2018).. To calculate the diagnostic gain obtained from calculating the Aß1-42/Aß1-40 ratio with respect to the exclusive use of the peptide Aß42 to identify patients belonging to the 'Alzheimer's disease contributes to mild cognitive impairment (MCI)' group, according to NIA-AA 2018 criteria.. Between April 2018 and April 2020, we included 62 patients with MCI, according to Petersen's 2006 criteria, who underwent lumbar puncture as part of the diagnostic process. Cerebrospinal fluid was analysed using the immunochemiluminescence methodology, which makes it possible to quantify core AD biomarkers in cerebrospinal fluid and the peptide Aß1-40.. Forty-two patients (67.7%) presented criteria supporting 'AD contributes to MCI'. The use of the Aß1-42/Aß1-40 ratio, compared to the exclusive use of Aß1-42 levels, represents a diagnostic gain of 19% (eight patients) to establish the presence of amyloidosis in the cerebrospinal fluid of these patients.. The calculation of the Aß1-42/Aß1-40 ratio is a clear diagnostic gain for identifying patients belonging to the 'AD contributes to MCI' group, and we therefore recommend its use, as reported in the most recent literature. To our knowledge, this is the first publication of its kind in Spanish.. Aportación del cociente Aß1-42/Aß1-40 al concepto ‘enfermedad de Alzheimer contribuye al deterioro cognitivo leve’.. Introducción. La demostración de amiloidosis cerebral, mediante la alteración de los niveles del péptido Aß1-42 o del cociente Aß1-42/Aß1-40, es condición necesaria para aceptar la presencia de la enfermedad de Alzheimer (EA), según los criterios de 2018 del National Institute on Aging y la Alzheimer’s Association (NIA-AA 2018). Objetivo. Calcular la ganancia diagnóstica que supone el cálculo del cociente Aß1-42/Aß1-40 respecto al uso exclusivo de los niveles del péptido Aß42 para identificar a los pacientes que pertenecen al grupo ‘EA contribuye al deterioro cognitivo leve (DCL)’, según los criterios NIA-AA 2018. Pacientes y métodos. Entre abril de 2018 y abril de 2020, incluimos a 62 pacientes con DCL, según los criterios de Petersen de 2006, a los que se les realizó una punción lumbar dentro del proceso diagnóstico. El líquido cefalorraquídeo se analizó mediante la metodología inmunoquimioluminiscente, que permite cuantificar los biomarcadores core de la EA en el líquido cefalorraquídeo y el péptido Aß1-40. Resultados. Cuarenta y dos pacientes (67,7%) presentaron criterios de ‘EA contribuye a DCL’. La utilización del cociente Aß1-42/Aß1-40, respecto a la utilización exclusiva de los niveles de Aß1-42, supone una ganancia diagnóstica del 19% (ocho pacientes) para establecer la presencia de amiloidosis en el líquido cefalorraquídeo de estos pacientes. Conclusión. El cálculo del cociente Aß1-42/Aß1-40 supone una ganancia diagnóstica clara para identificar a los pacientes que pertenecen al grupo ‘EA contribuye al DCL’, por lo que aconsejamos su utilización, como se viene recogiendo en la bibliografía más reciente. En nuestro conocimiento, es la primera publicación de estas características en lengua española.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Female; Humans; Male; Peptide Fragments; Retrospective Studies; Sensitivity and Specificity

The present study was conducted to evaluate the efficacy of fenofibrate and pioglitazone in a mouse model of amyloidogenesis induced by amyloidβ (βA) peptide. Mice were injected intracerebroventricularly with βA1-40 (400 pmol/mouse) once, followed by treatment with fenofibrate (300 mg/kg), pioglitazone (30 mg/kg),or both. After 21 days of daily treatment, memory impairment and cognitive function were evaluated by Morris water maze (MWM), Y-maze and object recognition tests. On the 22nd day, mice were sacrificed, and their hippocampi were dissected to determine the levels of α- and β-secretase, peroxisome proliferator-activated receptor (PPARα and β), Wnt and β-catenin. Significant memory impairment and cognitive dysfunction were observed in the mouse model group. This finding was associated with a significant increase in α- and β-secretase levels and a significant decrease in Wnt, β-catenin, and PPARα and β levels. Neuronal damage was also evident after histopathological examination. Treatment with fenofibrate, pioglitazone and their combination resulted in a significant improvement in the behavioural and neurochemical changes induced by βA injection. The present findings indicate that the combined administration of fenofibrate and pioglitazone was more effective than monotherapy in ameliorating the behavioural, neurochemical and histopathological changes in amyloidogenesis model mice and provide a promising therapeutic approach in the management of Alzheimer's disease complicated by diabetes and hypercholesterolemia.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Cognitive Dysfunction; Fenofibrate; Hippocampus; Infusions, Intraventricular; Male; Memory Disorders; Mice; Neuroprotective Agents; Peptide Fragments; Pioglitazone; PPAR alpha; PPAR gamma; Wnt Signaling Pathway

Recently, many studies have investigated the association between orexin A and Alzheimer's disease (AD). However, it remains to be determined whether the observed changes in orexin A levels are associated with pathological changes underlying AD, or cognitive function. In particular, a direct association between cerebrospinal fluid (CSF) orexin A levels and cognitive function has not been reported to date.. The aim of this study was to identify whether there is a direct association between the orexinergic system and cognitive function in AD.. For this study, we included 22 patients with AD and 25 control subjects who underwent general physical, neurological, and psychiatric examinations, neuroimaging, and CSF collection by lumbar puncture were enrolled. Correlations between CSF orexin A levels and CSF AD biomarker levels (i.e., levels of phosphorylated tau [p-tau], Aβ42, and Aβ42/Aβ40) were assessed to confirm the results of previous studies. Moreover, the correlation between CSF orexin A levels and Mini-Mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) scores were analyzed.. There was a significant positive correlation between CSF orexin-A levels and cognitive function (MMSE scores: r = 0.591, p = 0.04, MoCA score: r = 0.571, p = 0.006) in AD patients.. This is the first study to our knowledge demonstrating an association between cognitive function and CSF orexin A levels in AD. Our results suggest the possibility that orexinergic system overexpression is not always a negative factor for cognitive function In AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition; Cognitive Dysfunction; Female; Humans; Japan; Male; Mental Status and Dementia Tests; Middle Aged; Neuroimaging; Orexins; Peptide Fragments; tau Proteins

The aim of this study is to investigate the protective effects as well as the underlying molecular mechanisms of geniposide in APP/PS1 transgenic mice.. APP/PS1 mice were subjected to intragastric administration of geniposide (50 mg/kg/d) for 8 weeks (including a 2-week behavior test). The novel object recognition (NOR) and the Morris water maze (MWM) tests were used for behavioral assessments. Aβ1-40 plaques in mice cortices and hippocampi are visualized with immunohistochemistical staining. ELISA was used to quantify the levels of soluble Aβ1-40 and Aβ1-42 in the hippocampus. Western blot was used to detect p-Akt/Akt, p-mTOR/mTOR and p-4E-BP1/4E-BP1 levels. The relative mRNA levels of Akt, mTOR and 4E-BP1 were quantified using real-time PCR (RT-PCR).. Geniposide alleviated cognitive impairment by improving the ability of novel object exploration, spatial memory, and reduced the level of Aβ in the brain of APP/PS1 mice. Geniposide possibly regulates mTOR-related proteins through modification of phosphorylation. Geniposide markedly lowered p-mTOR and p-Akt expressions while elevating p-4E-BP1 expression. Geniposide obviously reduced the relative mRNA levels of Akt and mTOR and increased the relative mRNA level of 4E-BP1.. Geniposide is able to alleviate cognitive impairments and cerebral damage in APP/PS1 mice, with its neuroprotective effects likely mediated via modulation of the mTOR signaling pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Iridoids; Male; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Peptide Fragments; Plaque, Amyloid; Signal Transduction; TOR Serine-Threonine Kinases

Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures.. Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma.. Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aβ40, and Aβ42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery.. Tau increased during surgery (1752%, p = 0.0001) and NFL rose seven days post-surgery (1090%, p < 0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aβ40 and Aβ42.. Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Anesthesia, General; Biomarkers; Cardiac Surgical Procedures; Central Nervous System Diseases; Cognitive Dysfunction; Extracorporeal Circulation; Female; Humans; Male; Middle Aged; Neurofilament Proteins; Otorhinolaryngologic Diseases; Peptide Fragments; tau Proteins

To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with CSF biomarkers of Alzheimer disease (AD).. We analyzed data from n = 449 cognitively normal participants (n = 209 healthy controls, n = 240 patients with SCD) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, 5 cognitive domain factor structure comprising learning and memory, executive functions, language abilities, working memory, and visuospatial functions. We compared groups in terms of global and domain-specific performance and correlated performance with different CSF markers of AD pathology.. Within the spectrum of clinically unimpaired (i.e., before mild cognitive impairment) cognitive performance, SCD is associated with minor deficits in memory, executive function, and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD.

Topics: Aged; Amyloid beta-Peptides; Case-Control Studies; Cognitive Dysfunction; Diagnostic Self Evaluation; Executive Function; Factor Analysis, Statistical; Female; Humans; Language; Language Tests; Learning; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Peptide Fragments; Phosphorylation; Spatial Navigation; tau Proteins

Acupuncture is widely used to treat various neurodegenerative diseases and can effectively improve cognitive and memory states in Alzheimer's disease. However, its mechanism is unclear. We speculated that the effect of acupuncture on cognitive function may be associated with reductions in the levels of Aβ and phosphorylated tau in the brain. In this experiment, 60 male Sprague-Dawley rats were randomly divided into control, model, electroacupuncture and nonacupoint groups. We perform electroacupuncture at Shenting (GV24) and bilateral Benshen (GB13) acupoints once a day for 4 weeks in electroacupuncture group (with 1 day of rest after every 6 days of treatment). The electroacupuncture group showed a better performance in cognitive-related behavior tests and significantly lowers the levels of Aβ, p-tau (s396) and p-tau (s404) in the hippocampus. These results may suggest that electroacupuncture at the GV24 and bilateral GB13 acupoints might improve cognitive functions in Alzheimer's disease by decreasing the levels of Aβ, p-tau (s396) and p-tau (s404) in the brain as these proteins are the main causes of neurological damage and cognitive dysfunction during the pathogenesis underlying Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Disease Models, Animal; Electroacupuncture; Hippocampus; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; tau Proteins

Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer's disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms.. Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status.. We included 372 nondemented elderly from the Alzheimer's Disease Neuroimaging Initiative cohort. All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels.. Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42, APOEɛ4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels.. Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis.

Topics: Age Factors; Aged; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Carbolines; Case-Control Studies; Cognitive Dysfunction; Contrast Media; Ethylene Glycols; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Middle Aged; Organ Size; Peptide Fragments; Positron-Emission Tomography; tau Proteins

One of the major challenges in diagnosing dementia with Lewy bodies (DLB) is the common co-morbid presence of amyloid pathology. To understand the putative role of altered amyloid-β (Aβ) metabolism in dementia with DLB, we analyzed levels of different cerebrospinal fluid (CSF) Aβ peptides (Aβ38, Aβ40, Aβ42) in DLB, Alzheimer's disease (AD), and cognitively normal controls.. CSF from patients with DLB (n = 72; age 68 ± 6 years; 10%F; Mini-mental State examination (MMSE) 23 ± 4), AD (n = 38; age 68 ± 6 years; 8%F; MMSE 22 ± 5), and cognitively normal controls (n = 38; age 67 ± 7 years; 13%F; MMSE 29 ± 2) was analyzed using the Meso Scale Discovery assay for human Aβ peptides. We performed general linear models to compare CSF Aβ peptide levels between groups. Associations between CSF Aβ peptides and MMSE score at baseline and longitudinal changes over time were assessed with linear mixed models.. For all three CSF Aβ peptides and compared to controls (Aβ38 2676 ± 703 pg/ml, Aβ40 6243 ± 1500 pg/ml, and Aβ42 692 ± 205 pg/ml), we observed lower levels in DLB (Aβ38 2247 ± 638, Aβ40 5432 ± 1340, and Aβ42 441 ± 185, p < 0.05), whereas AD patients showed only lower Aβ42 levels (304 ± 71, p < 0.001). The observed differences in Aβ38 and Aβ40 were independent of co-morbid AD pathology (CSF tau/Aβ42 > 0.52) and APOE genotype. Finally, lower Aβ peptide levels were associated with lower MMSE score (β = 1.02-1.11, p < 0.05).. We demonstrated different profiles of CSF Aβ reduction in DLB and AD. In particular, while AD is characterized by an isolated drop in Aβ42, DLB comes with reductions in Aβ38, Aβ40, and Aβ42. This suggests that amyloid metabolism is affected in DLB, even in the absence of co-morbid AD pathology.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Humans; Lewy Body Disease; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments

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

Assessment of hippocampal amnesia is helpful to distinguish between normal cognition and mild cognitive impairment (MCI), but not for identifying converters to dementia. Here biomarkers are useful but novel neuropsychological approaches are needed in their absence. The In-out-test assesses episodic memory using a new paradigm hypothesized to avoid reliance on executive function, which may compensate for damaged memory networks.. To assess the validity of the In-out-test in identifying prodromal Alzheimer's disease (PAD) in a clinical setting, by comparing this to the Free and Cued Selective Reminding Test (FCSRT) and cerebrospinal fluid biomarkers.. A cross-sectional study of 32 cognitively healthy, 32 MCI, and 30 progressive dementia subjects. All participants were given both the In-out-test and the FCSRT; 40 of them also received a lumbar puncture.. Internal consistency was demonstrated using Cronbach Alpha (r = 0.81) and Inter-rater reliability with Kappa (k = 0.94). Intraclass correlation (ICC) for test-retest reliability: r = 0.57 (p = 0.57). ICC between the In-out-test and FCSRT r = 0.87 (p = 0.001). ICC between the In-out-test and Aβ42 and P-tau/Aβ42 for controls: 0.73 and 0.75, respectively; P-tau for MCI: 0.77 and total sample: 0.70; Aβ42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤0.264. AD diagnosis: In-out-test k = 0.71; FCSRT k = 0.49. PAD diagnosis (N = 35): In-out-test k = 0.69; FCSRT k = 0.44.. The In-out-test detected prodromal AD with a higher degree of accuracy than a conventional hippocampal-based memory test. These results suggest that this new paradigm could be of value in clinical settings, predicting which patients with MCI will go on to develop AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Cues; Female; Humans; Male; Memory Disorders; Memory, Episodic; Middle Aged; Neuropsychological Tests; Peptide Fragments; Reproducibility of Results; 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

Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer's disease (AD) in large population screening strategies.. This study evaluated the potential of plasma β-amyloid (Aβ) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years.. Total plasma Aβ42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern.. Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF).. TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Early Diagnosis; Female; Fluorodeoxyglucose F18; Genotype; Humans; Male; Neuroimaging; Peptide Fragments; Phosphorylation; Plaque, Amyloid; Positron-Emission Tomography; Prodromal Symptoms; tau Proteins; Thiazoles

The roots of Achyranthes bidentata Blume (AB) is commonly used in the treatment of osteoporosis and dementia in traditional Chinese medicine. Pharmacological reports evidenced that AB possessed anti-osteoarthritis effects. However, there is little literature about the anti-dementia activities of AB. The present study was designed to prepare steroid-enriched fraction of AB (ABS) and investigate whether ABS can protect from cognitive dysfunction and neuroinflammation against Aβ 1-40-induced Alzheimer's disease (AD) model in rats. ABS only contained 135.11 ± 4.28 mg of ecdysterone per gram. ABS (50 mg/kg) reversed the dysfunction of exploratory activity and memory function on plus-maze and Morris water maze caused by Aβ 1-40 in rats. ABS (50 mg/kg) also decreased amyloid deposition, neurofibrillary tangle, neural damage, activated astrocyte, and microglial caused by Aβ 1-40. Furthermore, ABS reversed the phenomenon of neural oxidative damage and neuroinflammation, including the higher levels of MDA and cytokines, and the lower activities of antioxidant enzymes and GSH levels caused by Aβ 1-40 in rat cortex and hippocampus. Finally, ABS restored the activation of ERK pathway and decreased NF-κB phosphorylation and translocation altered by Aβ 1-40. ABS alone (50 mg/kg) promoted cognitive function, activated brain antioxidant defense system, and decreased brain TNF-α levels in sham group. Therefore, ABS has the cognition-promoting and antidementia potential. Steroids especial ecdysterone are major active components of AB. The action mechanism is due to decreasing oxidative stress and neuroinflammation through modulating ERK pathway, NF-κB phosphorylation, and translocation in Aβ 1-40-induced AD rat model.

Topics: Acetylcholinesterase; Achyranthes; Amyloid beta-Peptides; Animals; Antioxidants; Astrocytes; Behavior, Animal; Brain; Cognitive Dysfunction; Cytokines; Ecdysterone; Glutathione; Hippocampus; Inflammation; Male; Malondialdehyde; MAP Kinase Signaling System; Maze Learning; Memory; Microglia; Neuroprotective Agents; NF-kappa B; Oleanolic Acid; Peptide Fragments; Rats, Sprague-Dawley; Steroids; Triterpenes; Ursolic Acid

The neurotoxicity of anesthetics on developing brain has been a focused issue for years. However, controversy exists between human and animal studies and surgery may be a potential reason for this. The discovery of glymphatic system, a pathway eliminating soluble substance from central nervous system (CNS), together with recent evidence that surgery-induced Aβ increase contributes to cognition dysfunction made us rethink about the influence of anesthetics on cognitive function. The function of glymphatic system was proved to be enhanced by sleep and sedation, so we assumed that under clinical situation Aβ1-40 whose accumulation played important role in cognitive dysfunction was increased by surgery and eliminated from CNS by glymphatic system. The function of glymphatic system is facilitated by aquaporin-4 (AQP-4), a water channel expressed in highly polarized manor in astrocytic endfeet, whose transcription is regulated by nuclear factor of activated T cells 5 (NFAT5). Our results suggest that under brief operation and sevoflurane exposure, surgery may be the main cause of Aβ increase and sevoflurane increase the elimination of Aβ by up-regulating AQP-4 which is the key component in glymphatic system.

Topics: Amyloid beta-Peptides; Animals; Aquaporin 4; Astrocytes; Brain; Central Nervous System; Cognitive Dysfunction; Glymphatic System; Hippocampus; Male; NFATC Transcription Factors; Peptide Fragments; Rats; Rats, Sprague-Dawley; Sevoflurane; Transcriptional Activation; Up-Regulation

Biological sex exerts distinct influences on brain levels of the β-amyloid (Aβ) peptide in both clinical depression and Alzheimer disease (AD), yet studies in animal models focus primarily on males. We examined behavioral 'despair'/depression (using the tail-suspension test) and memory (using the novel object recognition task) in J20 (hAPP

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognitive Dysfunction; Depression; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Transgenic; Peptide Fragments

Brain amyloid-β (Aβ) deposition is a hallmark to define Alzheimer's disease (AD). We investigated the positive rate of brain amyloid deposition assessed with 11C-Pittsburgh compound (PiB)-PET and blood Aβ levels in a cohort of probable AD patients who were diagnosed according to the 1984 NINCDS-ADRDA criteria. Eighty-four subjects with a clinical diagnosis of probable AD dementia, amnestic mild cognitive impairment (MCI), and cognitively normal (CN) status were subjected to PiB-PET and 18F-fluorodeoxyglucose (FDG)-PET scans. Plasma biomarkers of Aβ42, Aβ40, and T-tau were measured using single molecule array technology. The positive rate of PiB-PET, the associations between PiB-PET status and FDG-PET, plasma biomarkers, and clinical manifestations were analyzed. PiB-PET was positive in 77.36% of probable AD patients, 31.80% of MCI patients, and 0 of NC. Plasma Aβ42/Aβ40 ratio was associated with PiB-PET, the ROC curve analysis revealing an AUC of 0.77 (95% CI: 0.66-0.87), with a sensitivity of 82% and specificity of 64%. Some clinical manifestations were associated with PiB-PET imaging. Our findings indicate that only three-fourths of patients diagnosed with probable AD fit the pathological criteria, suggesting that we should be cautious regarding the accuracy of AD diagnosis when no biomarker evidence is available in our clinical practice.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Cognitive Dysfunction; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; tau Proteins

Alzheimer's disease currently lacks treatment options that effectively reverse the biological/anatomical pathology and cognitive deficits associated with the disease. Loss of function of the nuclear receptor REV-ERB is associated with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examined. In this study, we tested the hypothesis that enhanced REV-ERB function may enhance cognitive function in a model of Alzheimer's disease. We utilized the REV-ERB agonist SR9009 to pharmacologically activate the activity of REV-ERB in the SAMP8 mouse model of Alzheimer's disease. SR9009 reversed cognitive dysfunction of an aged SAMP8 mouse in several behavioral assays including novel object recognition, T-maze foot shock avoidance, and lever press operant conditioning task assessments. SR9009 treatment reduced amyloid-β 1-40 and 1-42 levels in the cortex, which is consistent with improved cognitive function. Furthermore, SR9009 treatment led to increased hippocampal PSD-95, cortical synaptophysin expression and the number of synapses suggesting improvement in synaptic function. We conclude that REV-ERB is a potential target for treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Disease Models, Animal; Disks Large Homolog 4 Protein; Hippocampus; Male; Mice; Nuclear Receptor Subfamily 1, Group D, Member 1; Peptide Fragments; Pyrrolidines; Thiophenes

Background Arterial stiffness is associated with cognitive decline and dementia; however, the precise mechanisms by which it affects the brain remain unclear. Methods and Results Using a mouse model based on carotid calcification this study characterized mechanisms that could contribute to brain degeneration due to arterial stiffness. At 2 weeks postcalcification, carotid stiffness attenuated resting cerebral blood flow in several brain regions including the perirhinal/entorhinal cortex, hippocampus, and thalamus, determined by autoradiography ( P<0.05). Carotid calcification impaired cerebral autoregulation and diminished cerebral blood flow responses to neuronal activity and to acetylcholine, examined by laser Doppler flowmetry ( P<0.05, P<0.01). Carotid stiffness significantly affected spatial memory at 3 weeks ( P<0.05), but not at 2 weeks, suggesting that cerebrovascular impairments precede cognitive dysfunction. In line with the endothelial deficits, carotid stiffness led to increased blood-brain barrier permeability in the hippocampus ( P<0.01). This region also exhibited reductions in vessel number containing collagen IV ( P<0.01), as did the somatosensory cortex ( P<0.05). No evidence of cerebral microhemorrhages was present. Carotid stiffness did not affect the production of mouse amyloid-β (Aβ) or tau phosphorylation, although it led to a modest increase in the Aβ40/Aβ42 ratio in frontal cortex ( P<0.01). Conclusions These findings suggest that carotid stiffness alters brain microcirculation and increases blood-brain barrier permeability associated with cognitive impairments. Therefore, arterial stiffness should be considered a relevant target to protect the brain and prevent cognitive dysfunctions.

Topics: Amyloid beta-Peptides; Animals; Behavior, Animal; Brain; Carotid Arteries; Carotid Artery Diseases; Cerebrovascular Circulation; Cognition; Cognitive Dysfunction; Collagen Type IV; Disease Models, Animal; Male; Mice, Inbred C57BL; Peptide Fragments; Spatial Memory; tau Proteins; Time Factors; Vascular Calcification; Vascular Stiffness

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40-converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE

Topics: Adult; Aged; Alzheimer Disease; Amyloid beta-Peptides; Angiotensin-Converting Enzyme Inhibitors; Animals; Cognitive Dysfunction; Female; Gene Deletion; Heterozygote; Humans; Longitudinal Studies; Male; Mice; Mice, Transgenic; Middle Aged; Peptide Fragments; Peptidyl-Dipeptidase A

The pathogenesis of Alzheimer's disease (AD) is associated with an increased inflammatory response via activated microglia and astrocytes. In the present study, we investigated whether treatment with the anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody adalimumab can improve cognitive function and reduce AD pathology in Aβ

Topics: Adalimumab; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Male; Memory; Mice, Inbred ICR; Neurons; Neuroprotective Agents; NF-kappa B; Peptide Fragments; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer's disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Biomarkers; Brain; Cell Line, Tumor; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Peptide Fragments; Proteolysis; Rats; Rats, Sprague-Dawley

Although it is known that Alzheimer's disease (AD) is associated with the progressive accumulation of amyloid β-peptide (Aβ) in the human brain, its pathogenic role has to be completely clarified. Aβ moves from the bloodbrain barrier to the plasma and an increased Aβ production in brain could be associated with higher Aβ concentrations in blood. A recent study has evaluated Aβ40 and Aβ42 levels in human red blood cells (RBCs) with evidence of agedependent higher Aβ concentration in RBCs.. The aim of the study was to investigate if erythrocyte associated Aβ (iAβ) levels could be different in subjects affected by dementia in comparison with controls and according to the patient's cognitive impairment or different dementia subtypes.. To answer these questions we assessed iAβ40 and iAβ42 levels in 116 patients: 32 healthy controls, 39 with diagnosis of vascular dementia (VaD), 14 mild cognitive impairment (MCI) and 31 AD.. In this population we found significant differences in iAβ42 between controls and cognitive impaired patients. Moreover, iAβ42 significantly differed between dementia vs MCI. AD also showed different iAβ42 levels as compared to VaD. Conversely, no differences were found for iAβ40. All the analyses were adjusted for potential confounders like age, gender and Hb concentration. A direct correlation between increasing iAβ42 concentration and the progression of the cognitive decline using the MMSE score as continuous variable was also found.. Our findings support the evidence that iAβ42 could be an instrument to early recognize dementia and predict cognitive impairment.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Cognitive Dysfunction; Correlation of Data; Dementia, Vascular; Erythrocytes; Female; Humans; Male; Mental Status Schedule; Peptide Fragments

Diabetes has been identified to be a risk factor for Alzheimer's disease (AD). Vildagliptin, a novel oral hypoglycemic agent, has been demonstrated to exert protective effects on the pancreas and cardiovascular system. The present study examined the potential protective effects of vildagliptin on neurons in an AD rat model. Treatment with vildagliptin improved memory deficits and decreased neuronal apoptosis in the hippocampus. The expression levels of B cell lymphoma 2 (Bcl‑2) were increased, and the expression levels of caspase‑3, Bcl‑2 associated X protein and AD‑associated proteins were decreased in the hippocampus following treatment with vildagliptin. Additionally, the AD model‑induced decrease in phosphorylated (p) protein kinase B (p‑Akt), p‑glycogen synthase kinase 3β (p‑GSK3β), post‑synaptic density 95 and synaptophysin expression was reversed. These results indicate that vildagliptin administration exerts a protective effect against cognitive deficits by reducing tau phosphorylation and increasing the expression of proteins associated with synaptic plasticity in the hippocampus. Targeting of the Akt/GSK3β signaling pathway may be a key mechanism in preventing the disease progression of AD.

Topics: Adamantane; Alzheimer Disease; Amyloid beta-Peptides; Animals; bcl-2-Associated X Protein; Caspase 3; Cognitive Dysfunction; Disease Models, Animal; Disks Large Homolog 4 Protein; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Hippocampus; Injections, Intraventricular; Male; Maze Learning; Neurons; Neuroprotective Agents; Nitriles; Nootropic Agents; Peptide Fragments; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Pyrrolidines; Rats; Rats, Sprague-Dawley; Signal Transduction; Synaptophysin; tau Proteins; Vildagliptin

Mild cognitive impairment (MCI) has an increased rate of progression to dementia. Alterations of some metabolic factors, such as deficiency of vitamin D, are a risk factor for cognitive deterioration. Vitamin D is involved in the clearance of β-amyloid (Aβ) from the brain. We have reported that lymphocytes from Alzheimer's disease (AD) patients have an increased susceptibility to oxidative death by H2O2 exposure, but currently it is unknown if this characteristic is modifiable in vivo.. To determine if correction of low vitamin D levels protects lymphocytes from oxidative death and increases Aβ1-40 plasma levels in MCI and very early AD (VEAD) patients.. Sixteen MCI, 11 VEAD and 25 healthy control (HC) voluntaries were evaluated with the Clinical Dementia Rating (CDR), Montreal Cognitive assessment (MoCA), and Memory Index score (MIS). Lymphocyte death was measured by flow cytometry after 20h exposure to H2O2. In patients with low levels of vitamin D -11 MCI, 9 VEAD and 20 HC- lymphocyte H2O2-death, plasma Aβ1-40 levels and cognitive status were evaluated pre- and post-vitamin D supplementation for 6 months.. Lymphocytes from MCI and VEAD patients showed increased susceptibility to oxidative death at study entry. In MCI, but not VEAD patients, lymphocyte susceptibility to death and Aβ1-40 levels plasma levels improved after 6 months of vitamin D supplementation. In addition, cognitive status on follow-up (18 months) improved in MCI patients after vitamin D supplementation.. Vitamin D supplementation may be beneficial in MCI. The lack of effect in VEAD may be due to a more advanced stage or different characteristics of the neurodegenerative process.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cell Death; Cell Survival; Cells, Cultured; Cholecalciferol; Cognition; Cognitive Dysfunction; Female; Follow-Up Studies; Humans; Hydrogen Peroxide; Lymphocytes; Male; Middle Aged; Neuroprotective Agents; Nootropic Agents; Oxidative Stress; Peptide Fragments; Treatment Outcome

Despite a tremendous amount of information on the role of amyloid in Alzheimer's disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects.. We present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission.. Preclinical data suggest a beneficial effect of shorter Aβ forms within a limited dose range. Such a beneficial effect of Aβ40 on glutamate neurotransmission in human patients is absolutely necessary to reproduce clinical data on the ADAS-Cog in minimal cognitive impairment (MCI) patients with and without amyloid load, the effect of APOE genotype effect on the slope of the cognitive trajectory over time in placebo AD patients and higher sensitivity to cholinergic manipulation with scopolamine associated with higher Aβ in MCI subjects. We further derive a relationship between units of Aβ load in our model and the standard uptake value ratio from amyloid imaging. When introducing the documented clinical pharmacodynamic effects on Aβ levels for various amyloid-related clinical interventions in patients with low Aβ baseline, the platform predicts an overall significant worsening for passive vaccination with solanezumab, beta-secretase inhibitor verubecestat and gamma-secretase inhibitor semagacestat. In contrast, all three interventions improved cognition in subjects with moderate to high baseline Aβ levels, with verubecestat anticipated to have the greatest effect (around ADAS-Cog value 1.5 points), solanezumab the lowest (0.8 ADAS-Cog value points) and semagacestat in between. This could explain the success of many amyloid interventions in transgene animals with an artificial high level of Aβ, but not in AD patients with a large variability of amyloid loads.. If these predictions are confirmed in post-hoc analyses of failed clinical amyloid-modulating trials, one should question the rationale behind testing these interventions in early and prodromal subjects with low or zero amyloid load.

Topics: Algorithms; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Clinical Trials as Topic; Cognition; Cognitive Dysfunction; Computer Simulation; Disease Progression; Glutamic Acid; Humans; Models, Neurological; Muscarinic Antagonists; Peptide Fragments; Scopolamine; Synaptic Transmission; Treatment Outcome

Exposure to chronic stress or elevated glucocorticoid hormone levels in adult life has been associated with cognitive deficits and an increased risk for Alzheimer's disease (AD). Since exposure to stress during early life enhances stress-responsiveness and lastingly affects cognition in adult life, we here investigated; (i) whether chronic early life stress (ELS) affects AD pathology and cognition in middle-aged APPswe/PS1dE9 mice, and (ii) whether it is still possible to rescue these late effects by briefly blocking glucocorticoid receptors (GRs) at a translationally relevant, middle age. Transgenic APPswe/PS1dE9 mice were subjected to ELS by housing dams and pups with limited nesting and bedding material from postnatal days 2-9 only. In 6- and 12-month-old offspring, this resulted in enhanced hippocampal amyloid-β (Aβ)-40 and -42 levels, and in reduced cognitive flexibility, that correlated well with the Aβ42 levels. In parallel, CORT levels and BACE1 levels were significantly elevated. Surprisingly, blocking GRs for only 3 days at 12 months of age reduced CORT levels, reduced hippocampal Aβ40 and -42, and β-site APP-cleaving enzyme 1 (BACE1) levels, and notably rescued the cognitive deficits in 12-month-old APPswe/PS1dE9 mice. These mouse data demonstrate that exposure to stress during the sensitive period early in life influences later amyloid pathology and cognition in genetically predisposed, mutant mice, and as such, may increase AD vulnerability. The fact that a short treatment with a GR antagonist at middle age lastingly reduced Aβ levels and rescued the cognitive deficits after ELS, highlights the therapeutic potential of this drug for reducing amyloid pathology.

Topics: Age Factors; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Behavior, Animal; Cognitive Dysfunction; Corticosterone; Disease Models, Animal; Female; Hippocampus; Hormone Antagonists; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mifepristone; Peptide Fragments; Receptors, Glucocorticoid; Stress, Psychological

Cerebrospinal fluid (CSF) biomarkers have been used to increase the evidence of underlying Alzheimer's disease (AD) pathology in mild cognitive impairment (MCI). However, CSF biomarker-based classification often results in conflicting profiles with controversial prognostic value. Normalization of the CSF Aβ42 concentration to the level of total amyloid beta (Aβ), using the Aβ42/40 ratio, has been shown to improve the distinction between AD and non-AD dementia. Therefore, we evaluated whether the Aβ42/40 ratio would improve MCI categorization and more accurately predict progression to AD.. Our baseline population consisted of 197 MCI patients, of which 144 had a follow-up ≥ 2 years, and comprised the longitudinal study group. To establish our own CSF Aβ42/40 ratio reference value, a group of 168 AD-dementia patients and 66 neurological controls was also included. CSF biomarker-based classification was operationalized according to the framework of the National Institute of Aging-Alzheimer Association criteria for MCI.. When using the core CSF biomarkers (Aβ42, total Tau and phosphorylated Tau), 30% of the patients fell into the high-AD-likelihood (HL) group (both amyloid and neurodegeneration markers positive), 30% into the low-AD-likelihood group (all biomarkers negative), 28% into the suspected non-Alzheimer pathophysiology (SNAP) group (only neurodegeneration markers positive) and 12% into the isolated amyloid pathology group (only amyloid-positive). Replacing Aβ42 by the Aβ42/40 ratio resulted in a significant increase in the percentage of patients with amyloidosis (42-59%) and in the proportion of interpretable biological profiles (61-75%), due to a reduction by half in the number of SNAP cases and an increase in the proportion of the HL subgroup. Survival analysis showed that risk of progression to AD was highest in the HL group, and increased when the Aβ42/40 ratio, instead of Aβ42, combined with total Tau and phosphorylated Tau was used for biomarker-based categorization.. Our results confirm the usefulness of the CSF Aβ42/40 ratio in the interpretation of CSF biomarker profiles in MCI patients, by increasing the proportion of conclusive profiles and enhancing their predictive value for underlying AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Disease Progression; Female; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Psychiatric Status Rating Scales; Survival Analysis; tau Proteins

Aggregation and deposition of amyloid-β (Aβ) in the brain is the main pathological change of Alzheimer's disease (AD). Decreased Aβ42 in the cerebrospinal fluid has been confirmed as a biomarker of AD; however, the relationship between plasma Aβ and cognitive impairment is currently unclear.. The aim was to explore the relationship between plasma Aβ and cognitive impairment in a cross-sectional study.. A total of 1,314 subjects (age above 40) from a village in the suburbs of Xi'an, China were enrolled between October 8, 2014 and March 30, 2015. A validated Chinese version of the Mini-Mental State Examination and neuropsychological battery were used to assess cognition. Levels of plasma Aβ42 and Aβ40 were tested using commercial enzyme-linked immunosorbent assay. Relationship of plasma Aβ and cognitive impairment was analyzed using logistic regression analysis.. Of the enrolled subjects, 1,180 (89.80%) had normal cognition, 85 (6.47%) had possible cognitive impairment and 49 (3.73%) had probable cognitive impairment. Logistic regression analysis showed that the Aβ42/Aβ40 ratio (OR = 4.042, 95% CI: 1.248-11.098, p = 0.012) and plasma Aβ42 (OR = 1.036, 95% CI: 1.003-1.071, p = 0.031) was higher in the possible cognitive impairment than that in the normal cognition group. Furthermore, the plasma Aβ42/Aβ40 ratio was higher in the possible cognitive impairment group than that in the probable cognitive impairment group (OR = 0.029, 95% CI: 0.002-0.450, p = 0.011).. Levels of plasma Aβ42 and Aβ42/Aβ40 ratio were elevated in patients with possible cognitive impairment, indicating that plasma Aβ42 and Aβ42/Aβ40 ratio increases may be more pronounced in early stage of cognitive impairment.

Topics: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Cognitive Dysfunction; Community Health Planning; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Peptide Fragments; Retrospective Studies

Alzheimer's disease (AD) is characterized by early degeneration of cholinergic neurons and decreased levels of nerve growth factor (NGF). Thus, increasing the NGF levels by for instance encapsulated cell bio-delivery (ECB) is a potential treatment strategy. The results from our previous first-in-human studies on ECB of NGF to the basal forebrain cholinergic neurons were promising, but indicated some variability of long-term viability of the encapsulated cells and associated reduced NGF-release. Here we studied the effect of amyloid beta-peptides (Aβ), interleukin 1-beta (IL-1β), and CSF from AD, Lewy body dementia (LBD) or subjective cognitive impairment (SCI) patients on the NGF overproducing cell line NGC-0295. At physiological concentrations, neither Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Transformed; Cell Survival; Cerebrospinal Fluid; Cognitive Dysfunction; Epithelial Cells; Gene Expression Regulation; Humans; Interleukin-1beta; Lewy Body Disease; Nerve Growth Factor; Peptide Fragments; Retinal Pigment Epithelium; Staurosporine

There is strong association of Alzheimer's disease (AD) pathology with gait disorder and falls in older adults without dementia. The goal of the study was to examine the prevalence and severity of AD pathology in older adults without dementia who fall and sustain hip fracture.. Cerebrospinal fluid (CSF) was obtained from 168 hip fracture patients. CSF Aβ42/40 ratio, p-tau, and t-tau measures were dichotomized into normal vs. abnormal, and categorized according to the A/T/N classification.. Among the hip fracture patients, 88.6% of the cognitively normal (Clinical Dementia Rating-CDR 0; n = 70) and 98.8% with mild cognitive impairment (CDR 0.5; n = 81) fell in the abnormal biomarker categories by the A/T/N classification.. A large proportion of older hip fracture patients have CSF evidence of AD pathology. Preoperative determination of AD biomarkers may play a crucial role in identifying persons without dementia who have underlying AD pathology in perioperative settings.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cohort Studies; Female; Hip Fractures; Humans; Male; Mental Status and Dementia Tests; Peptide Fragments; Risk Factors; tau Proteins

Peripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aβ) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aβ species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results.. The Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(. Brain and plasma Aβ levels are partially correlated in individuals diagnosed with SCD. Aβ plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography

Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer's disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease.. In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer's clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein).. CSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ. These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Female; Gastrointestinal Microbiome; Humans; Male; Methylamines; Middle Aged; Peptide Fragments; tau Proteins

Plasma β-amyloid (Aβ) is a potential candidate for an Alzheimer's disease (AD) biomarker because blood is an easily accessible bio-fluid, which can be collected routinely, and Aβ is one of the major hallmarks of AD pathogenesis in the brain. However, the association between plasma Aβ levels and AD diagnosis is still unclear due to the instability and inaccurate measurements of plasma Aβ levels in the blood of patients with AD. If a consistent value of plasma Aβ from the blood can be obtained, this might help determine whether plasma Aβ is a potential biomarker for AD diagnosis.. We predicted the brain amyloid deposit by measuring the plasma Aβ levels. This cross-sectional study included 353 participants (215 cognitively normal, 79 with mild cognitive impairment, and 59 with AD dementia) who underwent Pittsburgh-compound B positron emission tomography (PiB-PET) scans. We treated a mixture of protease inhibitors and phosphatase inhibitors (MPP) and detected plasma Aβ42 and Aβ40 (MPP-Aβ42 and MPP-Aβ40) in a stable manner using xMAP technology.. MPP-Aβ40 and MPP-Aβ42/40 (MPP-Aβs) were significantly different between subjects with positive amyloid deposition (PiB+) and those with negative amyloid deposition (PiB-) (P < 0.0001). Furthermore, MPP-Aβ40 (P < 0.0001, r = 0.23) and MPP-Aβ42/40 ratio (P < 0.0001, r = -0.23) showed significant correlation with global PiB deposition (standardized uptake value ratio). In addition, our integrated multivariable (MPP-Aβ42/40, gender, age, and apolipoprotein E genotypes) logistic regression model proposes a new standard for the prediction of cerebral amyloid deposition.. MPP-Aβ might be one of the potential blood biomarkers for the prediction of PiB-PET positivity in the brain.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Male; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Thiazoles

Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R

Topics: Administration, Intranasal; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Brain; Cell Line; Cognition; Cognitive Dysfunction; Disease Models, Animal; Female; Memory Disorders; Mice, Inbred C57BL; Peptide Fragments; Peptides

Accumulating evidence suggests that the use of angiotensin-converting enzyme inhibitor (ACE-I) medication protects against cognitive decline in the elderly patients. We investigated whether ACE-I use was associated with higher plasma levels of amyloid-β (Aβ), possibly indicating improved Aβ clearance from brain to blood.. We measured and compared plasma concentrations of Aβ42, Aβ40, and creatinine in cognitively impaired individuals with amnestic mild cognitive impairment, probable Alzheimer's disease (AD) dementia, and mixed probable AD/vascular dementia.. Plasma Aβ42 levels and Aβ42/Aβ40 ratios of participants taking ACE-Is (n = 11) significantly exceeded ( t = 3.1, df = 19, P = .006; U = 24, P = .029, respectively) those not taking ACE-Is (n = 10).. This study is the first to show an association between ACE-I use and increased plasma Aβ42 level and Aβ42/Aβ40 ratio in cognitively impaired individuals. Future investigations should assess whether a possible ACE-I-induced increase in plasma Aβ42 indicates improved Aβ42 clearance from brain that contributes to protection from cognitive decline.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Angiotensin-Converting Enzyme Inhibitors; Cognitive Dysfunction; Creatine; Dementia, Vascular; Female; Humans; Hypertension; Male; Peptide Fragments

To elucidate an involvement of amyloid dysmetabolism in the pathophysiology of depression, we investigated associations of plasma amyloid-β (Aβ) levels with Alzheimer's disease-related changes in neuroimaging and cognitive dysfunction in patients with late-life depression. Higher plasma Aβ40, but not Aβ42 nor Aβ40/Aβ42 ratio, was associated with higher degree of parahippocampal atrophy and lower verbal fluency performance. Indeed, high plasma Aβ40 predicted poor cognitive prognosis of depressed patients with mild cognitive impairment. As an anti-depressive treatment, electroconvulsive therapy (ECT) resulted in a marginally significant reduction of plasma Aβ40 compared to pharmacotherapy alone, suggesting protective effects of ECT against amyloid dysmetabolism.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Antidepressive Agents; Cognitive Dysfunction; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Psychiatric Status Rating Scales

Although amyloid β peptide (Aβ) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role.. Multidisciplinary methods were used to demonstrate immune adherence capture of Aβ by erythrocytes and its deficiency in Alzheimer's disease (AD).. Aβ was shown to be subject to immune adherence at every step in the pathway. Aβ dose-dependently activated serum complement. Complement-opsonized Aβ was captured by erythrocytes via CR1. Erythrocytes, Aβ, and hepatic Kupffer cells were colocalized in the human liver. Significant deficits in erythrocyte Aβ levels were found in AD and mild cognitive impairment patients.. CR1 polymorphisms elevate AD risk, and >80% of human CR1 is vested in erythrocytes to subserve immune adherence. The present results suggest that this pathway is pathophysiologically relevant in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Animals; Case-Control Studies; Cognitive Dysfunction; Dose-Response Relationship, Drug; Erythrocytes; Female; Humans; Liver; Macaca fascicularis; Male; Mental Status and Dementia Tests; Microscopy, Electron; Middle Aged; Peptide Fragments; Protein Binding; Receptors, Complement

The immunoproteasome (iP) represents a specialized type of proteasomes, which plays an important role in the clearance of oxidant-damaged proteins under inflammatory and pathological conditions determining the outcome of various diseases. In Alzheimer's disease (AD)-like APPPS1 mice Aβ-deposition is paralleled by iP upregulation, most likely mediated through type I interferon induction. To define the impact of increased iP expression we crossed APPPS1 mice with mice deficient in the iP subunit LMP7 resulting in impaired iP function. While LMP7 deficient APPPS1 mice showed no major change in cerebral Aβ-pathology, we observed an altered cytokine response in microglia isolated from LMP7 deficient APPPS1 mice compared to LMP7 expressing APPPS1 control mice. The altered microglial cytokine profile upon iP deficiency in the presence of extracellular Aβ-pathology was associated with an improvement of Aβ-associated cognitive deficits typically present in APPPS1 mice. Our findings suggest a role for iP in the regulation of the innate immune response towards extracellular Aβ-pathology and indicate that inhibition of iP function can modulate the cognitive phenotype upon overexpression of Aβ.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cells, Cultured; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Female; Humans; Male; Mice, Transgenic; Microglia; Peptide Fragments; Proteasome Endopeptidase Complex

Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone.. In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting.. Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181).. We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Imaging, Three-Dimensional; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Psychiatric Status Rating Scales; tau Proteins

We used 115 complete datasets from MCI patients of the "Dementia Competence Network", a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndromes. Variables known to predict progression in MCI patients were selected a priori. Nine individual predictors were compared by receiver operating characteristic (ROC) curve analysis. ROC curves of the five best two-, three-, and four-parameter combinations were analyzed for significant superiority by a bootstrapping wrapper around a support vector machine with linear kernel. The incremental value of combinations was tested for statistical significance by comparing the specificities of the different classifiers at a given sensitivity of 85%.. Out of 115 subjects, 28 (24.3%) with MCI progressed to AD dementia within a mean follow-up period of 25.5 months. At baseline, MCI-AD patients were no different from stable MCI in age and gender distribution, but had lower educational attainment. All single biomarkers were significantly different between the two groups at baseline. ROC curves of the individual predictors gave areas under the curve (AUC) between 0.66 and 0.77, and all single predictors were statistically superior to Aβ40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81. The three-parameter combinations ranged from AUC 0.80-0.83, and the four-parameter combination from AUC 0.81-0.82. None of the predictor combinations was significantly superior to the two best single predictors (HCV and t-Tau). When maximizing the AUC differences by fixing sensitivity at 85%, the two- to four-parameter combinations were superior to HCV alone.. A combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations. This may have implications for clinical diagnosis and for selecting subjects for participation in clinical trials.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Disease Progression; Educational Status; Female; Follow-Up Studies; Hippocampus; Humans; Male; Neuropsychological Tests; Organ Size; Peptide Fragments; Phosphorylation; Prognosis; Sensitivity and Specificity; Support Vector Machine; tau Proteins

Visual assessment of amyloid positron emission tomographic (PET) images has been approved by regulatory authorities for clinical use. Several immunoassays have been developed to measure β-amyloid (Aβ) 42 in cerebrospinal fluid (CSF). The agreement between CSF Aβ42 measures from different immunoassays and visual PET readings may influence the use of CSF biomarkers and/or amyloid PET assessment in clinical practice and trials.. To determine the concordance between CSF Aβ42 levels measured using 5 different immunoassays and visual amyloid PET analysis.. The study included 262 patients with mild cognitive impairment or subjective cognitive decline from the Swedish BioFINDER (Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably) cohort (recruited from September 1, 2010, through December 31, 2014) who had undergone flutemetamol F 18 ([18F]flutemetamol)-labeled PET. Levels of CSF Aβ42 were analyzed using the classic INNOTEST and the newer modified INNOTEST, fully automated Lumipulse (FL), EUROIMMUN (EI), and Meso Scale Discovery (MSD) assays. Concentrations of CSF Aβ were assessed using an antibody-independent mass spectrometry-based reference measurement procedure.. The concordance of CSF Aβ42 levels and Aβ42:Aβ40 and Aβ42:tau ratios with visual [18F]flutemetamol PET status.. Of 262 participants (mean [SD] age, 70.9 [5.5] years), 108 were women (41.2%) and 154 were men (58.8%). The mass spectrometry-derived Aβ42 values showed higher correlations with the modified Aβ42-INNOTEST (r = 0.97), Aβ42-FL (r = 0.93), Aβ42-EI (r = 0.93), and Aβ42-MSD (r = 0.95) assays compared with the classic Aβ42-INNOTEST assay (r = 0.88; P ≤ .01). The signal in the classic Aβ42-INNOTEST assay was partly quenched by recombinant Aβ1-40 peptide. However, the classic Aβ42-INNOTEST assay showed better concordance with visual [18F]flutemetamol PET status (area under the receiver operating characteristic curve [AUC], 0.92) compared with the newer assays (AUCs, 0.87-0.89; P ≤ .01). The accuracies of the newer assays improved significantly when Aβ42:Aβ40 (AUCs, 0.93-0.95; P ≤ .01), Aβ42 to total tau (T-tau) (AUCs, 0.94; P ≤ .05), or Aβ42 to phosphorylated tau (P-tau) (AUCs, 0.94-0.95; P ≤ .001) ratios were used. A combination of the Aβ42:Aβ40 ratio and T-tau or P-tau level did not improve the accuracy compared with the ratio alone.. Concentrations of CSF Aβ42 derived from the new immunoassays (modified INNOTEST, FL, EI, and MSD) may correlate better with the antibody-independent mass spectrometry-based reference measurement procedure and may show improved agreement with visual [18F]flutemetamol PET assessment when using the Aβ42:Aβ40 or Aβ42:tau ratios. These findings suggest the benefit of implementing the CSF Aβ42:Aβ40 or Aβ42:tau ratios as a biomarker of amyloid deposition in clinical practice and trials.

Topics: Aged; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Area Under Curve; Benzothiazoles; Cerebral Cortex; Cognitive Dysfunction; Cohort Studies; Female; Humans; Immunoassay; Male; Peptide Fragments; Positron-Emission Tomography; Radiopharmaceuticals; ROC Curve; Sweden; tau Proteins

Alzheimer's disease (AD) is an age-associated neurodegenerative disorder that is associated with a progressive impairment of cognition. Acupuncture has protective effects, although the molecular mechanisms are largely unknown. The activation of peroxisome proliferator activated receptor γ (PPAR-γ) has an impact on the pathogenesis of AD.. To test the hypothesis that electroacupuncture (EA) confers therapeutic benefits through activation of PPAR-γ in a rat model of AD.. 80 male Sprague-Dawley rats were randomly divided into four groups (n=20 each): Control (healthy control group), Sham (sham-operated group), AD (untreated AD model group), and AD+EA (AD model group treated with EA). The AD model was induced in the latter two groups by injection of amyloid-β (Aβ)1-40 into the hippocampal CA1 area bilaterally. EA was administered at GV20 and BL23 six times per week for 4 weeks. The rats' behaviour was examined using the Morris water maze test, and protein expression of Aβ, hyperphosphorylated tau protein (p-Tau), PPAR-γ, and hyperphosphorylated p38 mitogen activated protein kinase (p38MAPK) in the hippocampal CA1 region was examined by immunohistochemistry and Western blotting.. EA significantly improved cognitive deficits and reduced Aβ and p-Tau Ser404 protein concentrations in the hippocampal CA1 region. AD decreased PPAR-γ and increased p-p38MAPK, while EA significantly upregulated PPAR-γ expression and significantly downregulated p-p38MAPK expression.. Acupuncture at GV20 and BL23 might have a beneficial effect on rats with AD via activation of PPAR-γ and inhibition of p-p38MAPK expression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; CA1 Region, Hippocampal; Cognitive Dysfunction; Disease Models, Animal; Electroacupuncture; Immunohistochemistry; Male; Peptide Fragments; PPAR gamma; Rats; Rats, Sprague-Dawley

There is substantial variation caused by preanalytical procedures in the measurement of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reported in the literature.. Determine whether the detergent Tween-20 improves diagnostic accuracy.. CSF proteins (Aβ42, Aβ40, total tau, and phosphorylated tau) were measured by standard ELISA, in uncentrifuged CSF with or without 0.05% Tween-20 from patients with AD or amnestic mild cognitive impairment, and healthy elderly controls. In the main study, collection tubes containing Tween-20 (Sarstedt 15 mL) were filled with 5 mL CSF to ensure consistent detergent concentration across subsequent aliquots into Corning 2 mL tubes. These latter were also the primary collection vessel for samples without Tween-20. The effect of centrifugation, and extra tube transfer of samples with Tween-20 were also examined.. 0.05% Tween-20 significantly increased mean measured CSF concentration of Aβ42 (30% ), Aβ40 (23% ), and total tau (4% ), but not phosphorylated tau. Generally, these increases were similar in all groups, although for Aβ42, the mean percentage increase with Tween-20 was slightly larger for AD. Areas under receiver-operator characteristic curves were similar whether Tween-20 was present or not. Centrifuged CSF without Tween-20 significantly reduced the measured concentration of Aβ42 versus non-centrifuged samples, a difference not seen when detergent was added. Similar CSF Aβ42 levels were found whether Tween-20 was added at collection in an extra tube or directly to the main collection tube.. Addition of Tween-20 to CSF did not improve differentiation of patients from controls.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Phosphorylation; Polysorbates; ROC Curve; Surface-Active Agents; tau Proteins

Determine whether (1) a relationship exists between plasma amyloid-β (Aβ)1- 40 and 1-42 peptide levels, brain volumetrics and cognitive performance in elderly individuals with and without amnestic mild cognitive impairment (aMCI), (2) plasma Aβ peptide levels differ between apolipoprotein E (APOE) ε4 carriers and non-carriers and (3) longitudinal changes in cognition and brain volume relate to Aβ levels.. Subjects with aMCI (n = 89) and normal cognition (n = 126) were drawn from the Sydney Memory and Aging Study (Sydney MAS), a population based study of non-demented 70-90 year old individuals; 39 Alzheimer's disease (AD) patients were recruited from a specialty clinic. Sydney MAS participants underwent brain MRI scans and were assessed on 19 cognitive measures and were APOE ε4 genotyped. Plasma levels of Aβ1-40 and 1-42 were quantified using ELISA.. Wave1 plasma levels of Aβ peptides and Aβ1-42/1-40 ratio were lower in aMCI and AD, and Aβ1-42 was positively associated with global cognition and hippocampal volume and negatively with white matter hyperintensities. The relationships of Aβ1-40 and Aβ1-42 were predominantly observed in ε4 allele carriers and non-carriers respectively. Longitudinal analysis revealed greater decline in global cognition and memory for the highest quintiles of Aβ1-42 and the ratio measure.. Plasma Aβ levels and the Aβ1-42/1-40 ratio are related to cognition and hippocampal volumes, with differential associations of Aβ1-40 and Aβ1-42 in ε4 carriers and non-carriers. These data support the Aβ sink model of AD pathology, and suggest that plasma Aβ measures may serve as biomarkers of AD.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Brain; Cognition; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Longitudinal Studies; Male; Memory; New South Wales; Organ Size; Peptide Fragments

Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT(1A)R) after intrahippocampal injections of amyloid-beta 1-40 (Aβ40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [(18)F]MPPF revealing an overexpression of 5-HT(1A)R in the hippocampus of patients with mild cognitive impairment. Because Aβ40 and Aβ42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT(1A)R reactivity by injecting them, separately, into the hippocampus or striatum of rats. [(18)F]MPPF in vitro autoradiography revealed that Aβ40 fibrils, but not Aβ42, were triggering an overexpression of 5-HT(1A)R in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Aβ42 fibrils caused more pathophysiological damages than Aβ40 fibrils. The mechanisms of Aβ40 fibrils-induced 5-HT(1A)R expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Corpus Striatum; Disease Models, Animal; Hippocampus; Immunohistochemistry; Injections; Male; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT1

The ability to detect preclinical Alzheimer's disease is of great importance, as this stage of the Alzheimer's continuum is believed to provide a key window for intervention and prevention. As Alzheimer's disease is characterized by multiple pathological changes, a biomarker panel reflecting co-occurring pathology will likely be most useful for early detection. Towards this end, 175 late middle-aged participants (mean age 55.9 ± 5.7 years at first cognitive assessment, 70% female) were recruited from two longitudinally followed cohorts to undergo magnetic resonance imaging and lumbar puncture. Cluster analysis was used to group individuals based on biomarkers of amyloid pathology (cerebrospinal fluid amyloid-β42/amyloid-β40 assay levels), magnetic resonance imaging-derived measures of neurodegeneration/atrophy (cerebrospinal fluid-to-brain volume ratio, and hippocampal volume), neurofibrillary tangles (cerebrospinal fluid phosphorylated tau181 assay levels), and a brain-based marker of vascular risk (total white matter hyperintensity lesion volume). Four biomarker clusters emerged consistent with preclinical features of (i) Alzheimer's disease; (ii) mixed Alzheimer's disease and vascular aetiology; (iii) suspected non-Alzheimer's disease aetiology; and (iv) healthy ageing. Cognitive decline was then analysed between clusters using longitudinal assessments of episodic memory, semantic memory, executive function, and global cognitive function with linear mixed effects modelling. Cluster 1 exhibited a higher intercept and greater rates of decline on tests of episodic memory. Cluster 2 had a lower intercept on a test of semantic memory and both Cluster 2 and Cluster 3 had steeper rates of decline on a test of global cognition. Additional analyses on Cluster 3, which had the smallest hippocampal volume, suggest that its biomarker profile is more likely due to hippocampal vulnerability and not to detectable specific volume loss exceeding the rate of normal ageing. Our results demonstrate that pathology, as indicated by biomarkers, in a preclinical timeframe is related to patterns of longitudinal cognitive decline. Such biomarker patterns may be useful for identifying at-risk populations to recruit for clinical trials.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Atrophy; Biomarkers; Cluster Analysis; Cognitive Dysfunction; Female; Hippocampus; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; White Matter

The variability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1-42/Aβ1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1-42 (area under the curve = 0.93). In MCI patients, the Aβ1-42/Aβ1-40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1-42/Aβ1-40 ratio in AD diagnosis need to be validated in large multi-center studies.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Automation, Laboratory; Biomarkers; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Male; Mental Status and Dementia Tests; Peptide Fragments; tau Proteins

Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need.. We investigated the plasma levels of Aβ, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline.. Aβ40 and Aβ42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aβ correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aβ42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aβ and inflammatory molecules was a strong predictor of prospective cognitive deterioration.. Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.

Topics: Adolescent; Adult; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cytokines; Disease Progression; Down Syndrome; Female; Humans; Longitudinal Studies; Male; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Middle Aged; Nerve Growth Factor; Neuropeptides; Neuroserpin; Peptide Fragments; Prospective Studies; Protein Precursors; Serpins; Tissue Plasminogen Activator; Young Adult

The sortilin-related receptor 1 (SORL1) gene, regulating the trafficking and recycling of amyloid precursor protein, has been related to Alzheimer's disease (AD) and mild cognitive impairment (MCI). The aim of the present study was to investigate the relationship between SORL1 polymorphisms, plasma concentrations of amyloid-beta (Aβ) isoforms, and AD and MCI susceptibility for a Han Chinese population in Taiwan.. Eight single-nucleotide polymorphisms (SNPs) in SORL1 and the apolipoprotein E gene (APOE) ε4 alleles were genotyped in 798 patients with AD, 157 patients with MCI, and 401 control subjects. Plasma concentrations of Aβ42, Aβ40, and neuropsychiatric tests for six different cognitive domains were examined.. Among the eight tested SNPs, SORL1 rs1784933 was most significantly associated with AD and MCI in our population. The G allele of rs1784933 exerted a protective effect and was associated with a reduced risk of AD (odds ratio [OR] = 0.75, p = 0.004) and MCI (OR = 0.69, p = 0.013). The significance remained after we adjusted for age, sex, and APOE ε4 alleles. For the overall participants, the plasma concentrations of Aβ42 were nominally significant for subjects carrying the rs1784933 G allele having a lower level than those without the G allele (p = 0.046). There was a similar trend for the G allele carriers to have a lower plasma Aβ40 level than noncarriers, but this was not significant. The nonsynonymous SNP rs2298813 was also related to a lower disease risk when AD and MCI were combined as a group (OR = 0.76, p = 0.035). However, there was no association between SORL1 genotypes and any of the six cognitive tests.. Findings from our study provide support for the effect of SORL1 gene on the disease risks and pathognomonic surrogates of AD/MCI. The interaction between SORL1 polymorphisms and Aβ formation requires further study.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Asian People; Cognitive Dysfunction; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; LDL-Receptor Related Proteins; Linkage Disequilibrium; Male; Membrane Transport Proteins; Mental Status Schedule; Neuropsychological Tests; Peptide Fragments; Polymorphism, Single Nucleotide; Statistics, Nonparametric; Taiwan

Our current knowledge about the anatomical substrate of impaired resting-state cortical oscillatory coupling in mild cognitive impairment is still rudimentary. Here, we show that both resting-state oscillatory coupling and its anatomical correlates clearly distinguish healthy older (HO) adults from individuals with amnestic mild cognitive impairment (aMCI). aMCI showed failures in neural-phase coupling of resting-state electroencephalographic alpha activity mostly evident between fronto-temporal and parietal regions. As oligomers of amyloid-beta (Aβ) are linked to synaptic dysfunction in Alzheimer's disease (AD), we further investigated whether plasma concentrations of these oligomers (Aβ40 and Aβ42) accounted for impaired patterns of oscillatory coupling in aMCI. Results revealed that decreased plasma Aβ42 was associated with augmented coupling of parieto-temporal regions in HO subjects, but no relationship was found in aMCI. Oscillatory coupling of frontal regions was also significantly reduced in aMCI carriers of the ε4 allele of the Apolipoprotein E (ApoE) compared to ε4 noncarriers, although neither neuroanatomical nor plasma Aβ changes accounted for this difference. However, the abnormal pattern of oscillatory coupling in aMCI was negatively related to volume of the angular gyrus, and positively related to volume of the precuneus and the splenium of the corpus callosum. Previous evidence suggests that all these regions are neuropathological targets of AD. The current study takes that scenario one step further, suggesting that this anatomical damage could be responsible for disrupted cortical oscillatory coupling in aMCI. Together, these data shed light on how the MCI status modifies anatomo-functional relationships underlying coordination of large-scale cortical systems in the resting-state.

Topics: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Apolipoprotein E4; Cerebral Cortex; Cognitive Dysfunction; Electroencephalography; Evoked Potentials; Female; Frontal Lobe; Humans; Male; Oscillometry; Parietal Lobe; Peptide Fragments; Reaction Time; Temporal Lobe

This work was prompted by the finding that Aβ1-17 (Aβ17) appeared to be the second-most abundant cerebrospinal fluid (CSF) Aβ fragment, after Aβ40. We developed an ELISA to quantify levels of Aβ17 directly accessible in plasma (DA17), recovered from the proteomic plasma matrix (RP17) and associated with the cellular pellet (CP17) that remained after plasma collection. Then, we used a sample of 19 healthy control (HC), 27 mild cognitive impairment (MCI), and 17 mild Alzheimer's disease (AD) patients to explore the association of the diagnostic groups with those direct markers, their ratios or the ratios with their Aβ40 or Aβ42 counterparts. After dichotomization (d) for the median of the sample population, logistic regression analysis showed that in the AD versus HC subgroup, subjects with a dDA/CP17 higher than the median had a significantly greater risk of being AD than those with marker levels equal to or below the median (odds ratio OR; 95% confidence interval; 17.21; 1.42-208.81). Subjects with dRP17/42 below the median had an increased likelihood of being MCI (20.00; 1.17-333.33) or AD (40.00; 1.87-1000) versus being HC, than those with dRP17/42 higher than the median. Although the confidence intervals are wide, these findings suggest that assessment of Aβ17 may increase the diagnostic performance of blood-based Aβ tests which might be developed into minimally invasive first-step screening tests for people with increased risk for AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Cognitive Dysfunction; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mass Spectrometry; Odds Ratio; Peptide Fragments

The increasing role of cerebrospinal fluid (CSF) biomarkers in the early diagnosis of Alzheimer's disease (AD) is reflected in recently published diagnostic and/or research criteria. A growing body of evidence suggests better diagnostic performance of the amyloid-β (Aβ)42/40 CSF concentration ratio compared to the Aβ42 concentration alone.. (a) to analytically validate two novel ELISAs capable to measure Aβ1-40 and Aβ1-42 in the CSF, and (b) to compare the diagnostic accuracies of Aβ1-42 and Aβ42/40 ratio.. In this study, (a) the novel Aβ1-40 and Aβ1-42 ELISAs (IBL International GmbH, Hamburg, Germany) have been analytically validated, and (b) a clinical study has been performed comparing the diagnostic performance of the CSF Aβ42/40 concentration ratio and the CSF Aβ42 concentration.. In the analytical part of the study, only marginal cross-reactivity (Aβ1-42 versus Aβ1-40) was observed; recoveries were in the range of 85-100% for the samples diluted 1 : 20-1 : 640 (Aβ1-40), and 92-104% for the samples diluted 1 : 20-1 : 320 (Aβ1-42). For Aβ1-40, the intra-assay imprecision was 2.1%, the inter-assay imprecision was 4.4%, and the inter-lot imprecision was 5.4 %. For Aβ1-42, the numbers were 3.1%, 6.2%, and 6.9%, respectively. The goodness of the fit of the average standard curves was >0.99 for both assays, and the imprecision of the optical densities in ten repetitions of the standard curves was ≤5% for all standards. In the clinical part, at the cut off value 691 pg/mL, Aβ1-42 showed sensitivity and specificity of 69.3% and 88.9%, respectively, whereas at the cut off value 0.06, the Aβ42/40 ratio showed significantly improved performance with sensitivity and specificity of 93.3% and 100%, respectively. The area under the ROC curve for Aβ42/40 (0.974) was highly significantly larger compared to Aβ1-42 concentration ROC curve (0.827, p < 0.0001).. (a) the novel Aβ1-40 and Aβ1-42 ELISA assays characterize with very good analytical performance; (b) we reconfirm that the CSF Aβ42/40 concentration ratio shows significantly better diagnostic performance compared to the CSF Aβ1-42 concentration alone.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Area Under Curve; Biomarkers; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Peptide Fragments; ROC Curve; Sensitivity and Specificity

BACE1 (beta site amyloid precursor protein cleaving enzyme 1) is the rate limiting protease in amyloid β production, hence a promising drug target for the treatment of Alzheimer's disease. Inhibition of BACE1, as the major β-secretase in vivo with multiple substrates, however is likely to have mechanism-based adverse effects. We explored the impact of long-term pharmacological inhibition of BACE1 on dendritic spine dynamics, synaptic functions, and cognitive performance of adult mice.. Sandwich enzyme-linked immunosorbent assay was used to assess Aβ40 levels in brain and plasma after oral administration of BACE1 inhibitors SCH1682496 or LY2811376. In vivo two-photon microscopy of the somatosensory cortex was performed to monitor structural dynamics of dendritic spines while synaptic functions and plasticity were measured via electrophysiological recordings of excitatory postsynaptic currents and hippocampal long-term potentiation in brain slices. Finally, behavioral tests were performed to analyze the impact of pharmacological inhibition of BACE1 on cognitive performance.. Dose-dependent decrease of Aβ40 levels in vivo confirmed suppression of BACE1 activity by both inhibitors. Prolonged treatment caused a reduction in spine formation of layer V pyramidal neurons, which recovered after withdrawal of inhibitors. Congruently, the rate of spontaneous and miniature excitatory postsynaptic currents in pyramidal neurons and hippocampal long-term potentiation were reduced in animals treated with BACE1 inhibitors. These effects were not detected in Bace1(-/-) mice treated with SCH1682496, confirming BACE1 as the pharmacological target. Described structural and functional changes were associated with cognitive deficits as revealed in behavioral tests.. Our findings indicate important functions to BACE1 in structural and functional synaptic plasticity in the mature brain, with implications for cognition.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Cognition; Cognitive Dysfunction; Dendritic Spines; Dose-Response Relationship, Drug; Enzyme Inhibitors; Exploratory Behavior; Humans; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Pyramidal Cells; Pyrimidines; Pyrimidinones; Synaptic Potentials; Thiazines; Thiophenes; Time Factors

Endosomal-lysosomal and autophagic dysregulation occurs in the hippocampus in prodromal Alzheimer disease (AD), but its relationship with β-amyloid (Aβ) and tau pathology remains unclear. To investigate this issue, we performed immunoblot analysis of hippocampal homogenates from cases with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment (MCI), and AD. Western blot analysis revealed significant increases in the acid hydrolase cathepsin D and early endosome marker rabaptin5 in the MCI group compared with AD, whereas levels of phosphorylated mammalian target of rapamycin proteins (pmTOR), total mammalian target of rapamycin (mTOR), p62, traf6, and LilrB2 were comparable across clinical groups. Hippocampal Aβ1-40 and Aβ1-42 concentrations and AT8-immunopositive neurofibrillary tangle density were not significantly different across the clinical groups. Greater cathepsin D expression was associated with global cognitive score and episodic memory score but not with mini mental state examination or advanced neuropathology criteria. These results indicate that alterations in hippocampal endosomal-lysosomal proteins in MCI are independent of tau or Aβ pathology.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Autophagy; Cognitive Dysfunction; Cohort Studies; Endosomes; Female; Hippocampus; Humans; Lysosomes; Male; Peptide Fragments; tau Proteins

The 42-amino acid fragment of amyloid β (Aβ1-42) in cerebrospinal fluid has continued to be important for detecting cerebral β-amyloidosis in Alzheimer's disease (AD). However, there are impediments to our ability to fully understand this measurement, including matrix interference and changes linked to apolipoprotein E (APOE) ε4 genotype. This study investigated matrix interference as a contributing factor for detecting AD in APOE ε4-negative patients by comparing total extractable Aβ1-42 to free Aβ1-42. It also examined the ratio of total Aβ1-42 to Aβ1-40, since changes relative to other Aβ peptides may provide a measurement of cerebral β-amyloidosis that is neutral to changes in APP metabolism. Total Aβ1-42 lost the diagnostic power for detecting AD, confirming a role for matrix in the diagnostic. However, when total Aβ1-42/Aβ1-40 was examined, the separation between groups was reestablished. This result was confirmed in a second sample set of unknown APOE status. These results confirmed that matrix interference in some cerebrospinal fluid samples appears to contribute to identifying AD patients and this can be compensated by using a total extracted Aβ1-42/Aβ1-40 ratio when matrix interference is small. It may be preferable to employ a total Aβ1-42/Aβ1-40 measurement, since this could minimize variability because of matrix and compensate for across patient differences. Aβ1-42 measurement in CSF has provided an important tool for early detection of AD. However, it appears that most assays measure a free fraction of Aβ1-42. This study examined total extracted Aβ1-42, since this would provide a more accurate assessment of Aβ1-42 in AD CSF. Total Aβ1-42 measurements alone were not good for detecting AD but total Aβ1-42/Aβ1-40 performed well.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Chromatography, High Pressure Liquid; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Peptide Fragments; ROC Curve; tau Proteins

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

A practical biomarker is required to facilitate the preclinical diagnosis of Alzheimer's disease (AD).. Plasma amyloid beta (Aβ)1-40, Aβ1-42, Aβn-40, and Aβn-42 peptides were measured at baseline and after 18 months in 771 participants from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging. Aβ peptide levels were compared with clinical pathology, neuroimaging and neuropsychological measurements.. Although inflammatory and renal function covariates influenced plasma Aβ levels significantly, a decrease in Aβ1-42/Aβ1-40 was observed in patients with AD, and was also inversely correlated with neocortical amyloid burden. During the 18 months, plasma Aβ1-42 decreased in subjects with mild cognitive impairment (MCI) and in those transitioning from healthy to MCI.. Our findings are consistent with a number of published plasma Aβ studies and, although the prognostic value of individual measures in any given subject is limited, the diagnostic contribution of plasma Aβ may demonstrate utility when combined with a panel of peripheral biomarkers.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Chi-Square Distribution; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography

Apolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aβ) and fibrillar brain Aβ measured by Pittsburgh compound B positron emission tomography ([(11)C]PiB PET) has not been assessed.. Ninety-six Alzheimer's Disease Neuroimaging Initiative participants with [(11)C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [(11)C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [(11)C]PiB uptake.. In APOE ε4- but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [(11)C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [(11)C]PiB binding compared with using APOE and plasma Aβ1-40/Aβ1-42 as separate terms.. The results suggest that plasma Aβ is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain; Cerebral Cortex; Cognitive Dysfunction; Female; Humans; Male; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Alzheimer's disease (AD) is an age-dependent neurodegenerative condition that causes a progressive decline in cognitive function. Accumulation of amyloid β-protein (Aβ) in the brain is a prominent feature of AD and related disorders. However, the levels of Aβ accumulation alone are not a reliable predictor of cognitive deficits. Aβ accumulates in AD brain in the form of parenchymal amyloid plaques and cerebral vascular deposits. Although both types of lesions can contribute to cognitive decline, their temporal impact remains unclear. Moreover, cerebral microvascular pathology is identified as an early driver of cognitive impairment. Here for the first time, we compared two transgenic mouse strains, Tg-5xFAD and Tg-SwDI, which exhibit similar onset and anatomical accumulation of Aβ, but with distinct parenchymal and microvascular compartmental deposition, respectively, to assess their impact on cognitive impairment. Cohorts of each line were tested at 3 and 6 months of age to assess the relationship between spatial working memory performance and quantitative pathology. At 3 months of age, Tg-SwDI mice with onset of cerebral microvascular amyloid were behaviorally impaired, while the Tg-5xFAD, which had disproportionately higher levels of total Aβ, soluble oligomeric Aβ, and parenchymal amyloid were not. However, at 6 months of age, behavioral deficits for both groups of transgenic mice were evident, as the levels of Aβ pathologies in the Tg-5xFAD accumulated to extremely high amounts. The present findings suggest early-onset cerebral microvascular amyloid deposition, that precedes high parenchymal levels of Aβ, may be an important early factor in the development of cognitive deficits.

Topics: Age Factors; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apolipoprotein E4; Cerebral Cortex; Cognitive Dysfunction; Humans; Maze Learning; Mice; Mice, Transgenic; Microvessels; Peptide Fragments; Presenilin-1; Reaction Time

The objective of this study was to assess cerebrospinal fluid (CSF) β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity in relation to Alzheimer's disease (AD) and to correlate the enzyme activity with protein markers of APP metabolism and axonal degeneration.. BACE1 activity and protein concentrations were measured and analyzed in 342 participants of the Alzheimer's Disease Neuroimaging Initiative, including 99 normal control, 75 stable mild cognitive impairment (MCI), 87 progressive MCI, and 79 AD dementia cases. All statistical analyses were Bonferroni corrected for multiple comparisons.. No significant differences between controls and any of the three patient groups were detected for BACE1 activity and soluble APPβ (sAPPβ) concentrations in CSF. Significant correlations with BACE1 activity were found for CSF APPβ and total tau in all four groups and for CSF phosphorylated tau181 in all groups but the progressive MCI group. There were no correlations for CSF amyloid β (Aβ)1-42 or for plasma Aβ1-42 and Aβ1-40.. The consistent correlation between BACE1 activity and sAPPβ supports their role as biomarkers of target engagement in clinical trials on BACE1 inhibition.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Axons; Biomarkers; Clinical Trials as Topic; Cognitive Dysfunction; Databases, Factual; Female; Humans; Male; Nerve Degeneration; Peptide Fragments; Phosphorylation; tau Proteins

To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers.. Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria.. The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1-42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1-42 and 1-40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold.. In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1-42 and 1-40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Intermediate Filament Proteins; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Peptide Fragments; Retrospective Studies; Severity of Illness Index; tau Proteins

A growing body of evidence shows the involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in neurodegeneration processes, but reports of their concentrations in the cerebrospinal fluid (CSF) are inconsistent.. Therefore, the aim of our study was to evaluate the CSF concentrations of MMP-2, MMP-3, MMP-9, and their inhibitors (TIMP-1 and TIMP-2) in carefully selected groups of patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and non-demented controls, whose clinical and neuropsychological diagnoses were confirmed by the corresponding CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio, and increased concentrations of Tau and pTau181 proteins.. The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of MMPs and TIMPs were determined with ELISAs.. CSF concentrations of MMP-9 were significantly lower, and the concentrations of MMP-3 significantly higher in AD patients compared to the controls. Neither MMP-2 nor TIMPs showed significant changes among the groups investigated.. Altered concentrations of two out of three MMPs investigated in this study suggest that this family of biomolecules may play a role in the AD pathophysiology. Further studies are needed to establish their potential diagnostic utility.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Middle Aged; Peptide Fragments; Retrospective Studies; Spinal Puncture; tau Proteins

We found previously that the amyloid β40/42 (Aβ40/42) ratio and the level of protein-conjugated acrolein (PC-Acro) in plasma were increased in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects. We determined whether MCI and AD subjects can be differentiated based on the levels of Aβ40, Aβ42, and PC-Acro in cerebrospinal fluid (CSF).. Aβ40, Aβ42, PC-Acro, Tau and phosphorylated Tau in CSF were measured by ELISA.. Median values of Aβ40, Aβ40/PC-Acro and Aβ40/42 in CSF were significantly lower in 54 AD subjects than those in 40 MCI subjects. Severity of VOI (volume of interest) atrophy was most intensely correlated with the decrease in Aβ40/PC-Acro and then that in Aβ40 and Aβ42/PC-Acro. MMSE was most intensely correlated with the decrease in Aβ42 and Aβ40, and then that in Aβ42/PC-Acro and Aβ40/PC-Acro.. A decrease in Aβ40/PC-Acro in CSF is well correlated with brain damage, and a decrease in Aβ42 and Aβ40 is well correlated with cognitive ability. Measurement of PC-Acro together with Aβ40 and Aβ42 provides a more precise evaluation of severity of AD subjects.

Topics: Acrolein; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Peptide Fragments

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

Transactive response DNA binding protein 43 (TDP-43) is detected in pathological inclusions in many cases of Alzheimer's disease (AD) and mild cognitive impairment (MCI), but its pathological role in AD and MCI remains unknown. Recently, TDP-43 was reported to contribute to pathogenesis in amyotrophic lateral sclerosis through its interaction with p65 nuclear factor κB (NF-κB) resulting in abnormal hyperactivation of this signaling pathway in motor neurons. Hence, we investigated the interaction of TDP-43 with p65 in the temporal cortex of subjects with a clinical diagnosis of MCI (n = 12) or AD (n = 12) as well as of age-matched controls with no cognitive impairment (NCI, n = 12).. Immunoprecipitation and immunofluorescence approaches revealed a robust interaction of TDP-43 with p65 in the nucleus of temporal lobe neurons in four individuals with MCI (named MCI-p). These MCI-p cases exhibited high expression levels of soluble TDP-43, p65, phosphorylated p65 and low expression levels of β-amyloid 40 when compared to AD or NCI cases. The analysis of cognitive performance tests showed that MCI-p individuals presented intermediate deficits of global cognition and episodic memory between those of AD cases and of NCI cases and MCI cases with no interaction of TDP-43 with p65.. From these results, we propose that enhanced NF-κB activation due to TDP-43 and p65 interaction may contribute to neuronal dysfunction in MCI individuals with episodic memory deficits. Accordingly, treatment with inhibitors of NF-κB activation may be considered for MCI individuals with episodic memory deficits.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoprecipitation; Longitudinal Studies; Male; Memory Disorders; Peptide Fragments; Statistics, Nonparametric; tau Proteins; Temporal Lobe; Transcription Factor RelA

Recent advances in biomarkers provide the possibility of early or preclinical diagnosis of Alzheimer's pathology. Currently, decreased levels of Aβ-42 and increased levels of tau proteins in cerebral spinal fluid are considered reliable biomarkers of Alzheimer's disease (AD); however, little evidence exists for the use of amyloid and tau protein levels in the plasma as useful biomarkers. We investigated the potential use of plasma biomarkers to diagnose AD and explored their relationships with brain Aβ deposition in amyloid imaging. We used an immunomagnetic reduction assay to measure the plasma levels of Aβ40, Aβ42, and tau proteins in 20 older control participants and 25 participants who had either mild cognitive impairment due to AD or early AD dementia. All participants received (11)C-labeled Pittsburgh compound B PET scans. The sensitivity of the plasma tau level at the cutoff value of 28.27 pg/mL was 92%, and the specificity was 100%; the sensitivity of the Aβ42/40 ratio at the cutoff value of 0.3693 was 84%, and the specificity was 100%. Regression analyses of the effects of plasma protein levels on brain amyloid retention, as determined by standard uptake value ratios in either side of the frontal, parietal, and temporal lobes and the precuneus, are predicted only by ratios of plasma Aβ42/40 (R(2) 0.326-0.449, all p < 0.001) but not by plasma tau levels. Plasma Aβ in terms of Aβ42/40 might provide an indirect estimation of Aβ deposition in the brain.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Chi-Square Distribution; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Psychiatric Status Rating Scales; Radionuclide Imaging; Regression Analysis; tau Proteins; Thiazoles

Cerebrospinal fluid (CSF) biomarkers β-amyloid 1-42 (Aβ1-42), also expressed as Aβ1-42:Aβ1-40 ratio, T-tau, and P-tau181P, have proven diagnostic accuracy for mild cognitive impairment and Alzheimer's disease (AD). How to use, interpret, and disclose biomarker results drives the need for standardization.. Previous Alzheimer's Biomarkers Standardization Initiative meetings discussed preanalytical issues affecting Aβ1-42 and tau in CSF. This second round of consensus meetings focused on issues related to clinical use of AD CSF biomarkers.. Consensus was reached that lumbar puncture for AD CSF biomarker analysis be considered as a routine clinical test in patients with early-onset dementia, at the prodromal stage or with atypical AD. Moreover, consensus was reached on which biomarkers to use, how results should be interpreted, and potential confounding factors.. Changes in Aβ1-42, T-tau, and P-tau181P allow diagnosis of AD in its prodromal stage. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Consensus; Diagnosis, Differential; Female; Humans; Male; Peptide Fragments; Reference Standards; tau Proteins

Plasma amyloid beta (Aβ) levels are being investigated as potential biomarkers for Alzheimer's disease. In AB128 cross-sectional study, a number of medical relevant correlates of blood Aβ40 or Aβ42 were analyzed in 140 subjects (51 Alzheimer's disease patients, 53 healthy controls and 36 individuals diagnosed with mild cognitive impairment). We determined the association between multiple variables with Aβ40 and Aβ42 levels measured in three different blood compartments called i) Aβ directly accessible (DA) in the plasma, ii) Aβ recovered from the plasma matrix (RP) after diluting the plasma sample in a formulated buffer, and iii) associated with the remaining cellular pellet (CP). We confirmed that diastolic blood pressure (DBP) is consistently correlated with blood DA Aβ40 levels (r=-0.19, P=0.032). These results were consistent in the three phenotypic groups studied. Importantly, the observation resisted covariation with age, gender or creatinine levels. Observed effect size and direction of Aβ40 levels/DBP correlation are in accordance with previous reports. Of note, DA Aβ40 and the RP Aβ40 were also strongly associated with creatinine levels (r=0.599, P<<0.001) and to a lesser extent to urea, age, hematocrit, uric acid and homocysteine (p<0.001). DBP and the rest of statistical significant correlates identified should be considered as potential confounder factors in studies investigating blood Aβ levels as potential AD biomarker. Remarkably, the factors affecting Aβ levels in plasma (DA, RP) and blood cell compartments (CP) seem completely different.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Blood Chemical Analysis; Blood Pressure; Case-Control Studies; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Peptide Fragments; Regression Analysis; Reproducibility of Results

We have used proteomic fingerprinting to investigate diagnosis of Alzheimer's disease (AD). Samples of lumbar cerebrospinal fluid (CSF) from clinically-diagnosed AD cases (n = 33), age-matched controls (n = 20), and mild cognitive impairment (MCI) patients (n = 10) were used to obtain proteomic profiles, followed by bioinformatic analysis that generated a set of potential biomarkers in CSF samples that could discriminate AD cases from controls. The identity of the biomarker ions was determined using mass spectroscopy. The panel of seven peptide biomarker ions was able to discriminate AD patients from controls with a median accuracy of 95% (sensitivity 85%, specificity 97%). When this model was applied to an independent blind dataset from MCI patients, the intensity of signals was intermediate between the control and AD patients implying that these markers could potentially predict patients with early neurodegenerative disease. The panel were identified, in order of predictive ability, as SPARC-like 1 protein, fibrinogen alpha chain precursor, amyloid-β, apolipoprotein E precursor, serum albumin precursor, keratin type I cytoskeletal 9, and tetranectin. The 7 ion ANN model was further validated using an independent cohort of samples, where the model was able to classify AD cases from controls with median accuracy of 84.5% (sensitivity 93.3%, specificity 75.7%). Validation by immunoassay was performed on the top three identified markers using the discovery samples and an independent sample cohort which was from postmortem confirmed AD patients (n = 17).

Topics: Algorithms; Alzheimer Disease; Amyloid beta-Peptides; Area Under Curve; Biomarkers; Calcium-Binding Proteins; Case-Control Studies; Cognitive Dysfunction; Cohort Studies; Computational Biology; Cytoskeleton; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Female; Fibrinogen; Humans; Male; Neural Networks, Computer; Peptide Fragments; Peptide Mapping; Proteomics; Psychiatric Status Rating Scales; ROC Curve; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; tau Proteins

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

Sporadic Alzheimer's disease (AD) patients have low amyloid-β peptide (Aβ) clearance in the central nervous system. The peripheral Aβ clearance may also be important but its role in AD remains unclear. We aimed to study the Aβ degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V (a substrate of IDE and other metalloproteases), we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Aβ. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin, or EDTA, and further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aβ degradation may be important for the AD pathogenesis. More studies are needed to specify each Aβ degrading protease in blood as a useful biomarker and a possible treatment target for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Brain; Cognitive Dysfunction; Female; Fluorescent Dyes; Humans; Insulysin; Islet Amyloid Polypeptide; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Peptide Fragments; Peptidyl-Dipeptidase A; Psychiatric Status Rating Scales; Serum; Statistics, Nonparametric; Time Factors

Although there is a consensus on the reduced levels of Aβ1-42 in the CSF of patients with AD, studies of plasma Aβ levels were inconsistent and have limited clinical value. We developed an immunomagnetic reduction assay (IMR) to determine the plasma levels of Aβ. We surveyed patients with varying AD severity (CDR = 0.5, n=16; CDR ≥ 1, n=18) and controls (n=26). Significant group differences were apparent in the levels of Aβ1-42 (F = 5.54, p = 0.002) and the Aβ1-42/Aβ1-40 ratio (F = 24.198, p < 0.001). Post-hoc analyses showed significant differences in the Aβ1-42 levels of controls and AD patients (p = 0.001) and in the Aβ1-42/Aβ1-40 ratio of control, MCI and AD subjects (all p ≤ 0.001). Regression analysis of Aβ1-42/Aβ1-40 ratios on dementia severity showed an adjusted R2 of 0.553 (p = 0.001). We identified a cut-off of 16.1 pg/ml for Aβ1-42 to differentiate control subjects from patients (both AD and MCI) with 85.3% sensitivity and 88.5% specificity. We also obtained a cut-off value of 0.303 for Aβ1-42/Aβ1-40 ratios with 85.3% sensitivity and 96.2% specificity. APOE 4 carriers had significantly higher Aβ1-42/Aβ1-40 ratios than the non-carriers (F = 4.839, p = 0.015). An independent group of case-control subjects validated both cut-off values for Aβ1-42/Aβ1-40 (100% sensitivity and 83.3% specificity) and for Aβ1-42 (100% sensitivity and 75.3% specificity). In a subgroup of longitudinal follow- up study, we found that the plasma Aβ was relatively stable with an interval of approximately 3 months. In conclusion, we found that the plasma Aβ1-42 is a useful biomarker for AD. The Aβ1-42/Aβ1-40 ratio improves the diagnostic power of the plasma Aβ biomarkers. The iron nanoparticles and IMR provides a novel method to measure plasma Aβ and could serve as an important clinical tool for the diagnosis of neurodegenerative diseases.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Immunomagnetic Separation; Magnetite Nanoparticles; Male; Middle Aged; Multivariate Analysis; Peptide Fragments; ROC Curve

Hippocampal precursor of nerve growth factor (proNGF)/NGF signaling occurs in conjunction with β-amyloid (Aβ) accumulations in Alzheimer disease (AD). To assess the involvement of this pathway in AD progression, we quantified these proteins and their downstream pathway activators in postmortem tissues from the brains of subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD using immunoblotting and ELISA. Hippocampal proNGF was significantly greater in AD cases compared with those in NCI and MCI cases. TrkA was significantly reduced in MCI compared with those in NCI and AD, whereas p75 neurotrophin receptor, sortilin, and neurotrophin receptor homolog 2 remained stable. Akt decreased from NCI to MCI to AD, whereas phospho-Akt and phospho-Akt-to-Akt ratio were elevated in AD compared with those in MCI and NCI. No differences were found in phospho-Erk, Erk, or their ratio across groups. Although c-jun kinase (JNK) remained stable across groups, phospho-JNK and the phospho-JNK-to-JNK ratio increased significantly in AD compared with those in NCI and MCI. Expression levels of Aβ(1-40), Aβ(1-42), and Aβ(40/42) ratio were stable. Statistical analysis revealed a strong positive correlation between proNGF and phospho-JNK, although only proNGF was negatively correlated with cognitive function and only TrkA was negatively associated with pathologic criteria. These findings suggest that alterations in the hippocampal NGF signaling pathway in MCI and AD favor proNGF-mediated proapoptotic pathways, and that this is independent of Aβ accumulation during AD progression.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Cognitive Dysfunction; Female; Hippocampus; Humans; Male; MAP Kinase Signaling System; Nerve Growth Factor; Peptide Fragments; Protein Precursors

Amyloid β(Aβ) peptides are important components of plaques in Alzheimer's disease(AD). A decrease in the CSF concentration of Aβ40 and Aβ42 is a potential biomarker for incident AD. In contrast, studies on plasma Aβ40 and Aβ42 concentrations have yielded contradictory results. To explore the relationship between plasma Aβ40 and Aβ42 concentrations and AD in aging individuals with mild cognitive impairment (MCI), evaluate the sensitivity and the specificity of plasma Aβ and their ratio as a marker for progression to AD. We measured baseline concentrations of Aβ40 and Aβ42, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias from a cohort of patients with MCI (n=588) after 4-6 years of follow-up time. Plasma concentrations of Aβ40, Aβ42 were measured using a sandwich enzyme-linked immunosorbent assay technology. The association between plasma Aβ concentrations and the risk of dementia was assessed using Cox proportional hazard models. Optimal sensitivity and specificity of Aβ measurements were determined by ROC curve analysis. Plasma Aβ42 concentration and the Aβ42/Aβ40 ratio at baseline were significantly decreased in the MCI patients who developed AD as compared to cognitively stable MCI patients. The baseline concentrations of Aβ40 were similar in all MCI groups. The Aβ42/Aβ40 ratio was superior to Aβ42 concentration with regard to identify incipient AD in MCI. The ratio of Aβ42 to Aβ40 rather than absolute levels of the peptides can aid in the identification of incipient AD among MCI patients. A potential role of plasma Aβ concentrations as a marker of incipient dementia warrants further investigation.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cohort Studies; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Peptide Fragments; Plaque, Amyloid; Prospective Studies