Plasma Proteomics Biomarkers in Alzheimer's Disease: Latest Advances and Challenges.

The recent paradigm shift towards a more biologically oriented definition of Alzheimer's disease (AD) in clinical settings increases the need for sensitive biomarkers that can be applied in population-based settings. Blood plasma is easily accessible and contains a large number of proteins related to cerebral processes. It is therefore an ideal candidate for AD biomarker discovery.

LRP-1 polymorphism is associated with global and regional amyloid load in Alzheimer's Disease in humans in-vivo.

Objective: Impaired amyloid clearance has been proposed to contribute to β-amyloid deposition in sporadic late-onset Alzheimer's disease (AD). Low density lipoprotein receptor-related protein 1 (LRP-1) is involved in the active outward transport of β-amyloid across the blood-brain barrier (BBB). The C667T polymorphism (rs1799986) of the LRP-1 gene has been inconsistently associated with AD in genetic studies.

Amyloid cascade and tau pathology cerebrospinal fluid markers in mild cognitive impairment with regards to Alzheimer's disease cerebral metabolic signature.

Background: Biomarker relationships in early stages of Alzheimer's disease (AD) are elusive. Cerebrospinal fluid (CSF) levels of amyloid-β 1-42 (Aβ42) and total tau (tTau) as well as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) contribute to help unravel AD pathology. Furthermore, peptides related to amyloid-β protein precursor (AβPP) processing [e.

Heart-type fatty acid binding protein and vascular endothelial growth factor: cerebrospinal fluid biomarker candidates for Alzheimer's disease.

The main objective of the study was to validate the findings of previous cerebrospinal fluid (CSF) proteomic studies for the differentiation between Alzheimer's disease (AD) dementia and physiological ageing. The most consistently significant proteins in the separation between AD dementia versus normal controls using CSF proteomics were identified in the literature. The classification performance of the four pre-selected proteins was explored in 92 controls, 149 patients with mild cognitive impairment (MCI), and 69 patients with AD dementia.

Plasma proteomics for the identification of Alzheimer disease.

Less-invasive biomarkers for early Alzheimer disease (AD) are urgently needed. The present study aimed to establish a panel of plasma proteins that accurately distinguishes early AD from physiological aging and to compare the findings with previous reports. Fifty-eight healthy controls (CON) and 109 patients with AD dementia were randomly split into a training (40%) and a test (60%) sample.

Brain size and the compensation of Alzheimer's disease symptoms: a longitudinal cohort study.

Background: Greater intracranial volume (ICV) has been associated with less severe Alzheimer's disease (AD) symptoms at a given level of cerebral pathology. In this study we examine whether ICV modulates the association between clinical disease progression on the one hand and brain atrophy or the apolipoprotein E genotype on the other.

Methods: Six hundred seventy-four subjects were studied from the AD Neuroimaging Initiative (ADNI).

β-Site amyloid precursor protein-cleaving enzyme 1 activity is related to cerebrospinal fluid concentrations of sortilin-related receptor with A-type repeats, soluble amyloid precursor protein, and tau.

Background: β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity determines the rate of APP cleavage and is therefore the main driver of amyloid β production, which is a pathological hallmark of Alzheimer's disease (AD).

Methods: The present study explored the correlation between BACE1 activity and cerebrospinal fluid (CSF) markers of APP metabolism and axonal degeneration in 63 patients with mild AD and 12 healthy control subjects.

Results: In the AD group, positive correlations between BACE1 activity and soluble APP β, the APP sorting receptor sortilin-related receptor with A-type repeats (also known as SorLA or LR11), and tau were detected.

The National Institute on Aging-Alzheimer's Association research criteria for mild cognitive impairment due to Alzheimer's disease: predicting the outcome.

The National Institute on Aging-Alzheimer's Association (NIA-AA) clinical research criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) incorporate the use of biomarkers to classify patients according to the likelihood of the presence of AD pathology. The aim of the study was to compare the risk of progression to AD dementia between the four NIA-AA MCI subgroups using data from the AD Neuroimaging Initiative. Patients with MCI were categorised according to the NIA-AA criteria into subgroups with high, intermediate, and low likelihood of the presence of AD pathology (MCI-high, MCI-intermediate, and MCI-unlikely, respectively) or into a group of patients that only met the MCI-core clinical criteria (MCI-core).

SORL1 genetic variants and cerebrospinal fluid biomarkers of Alzheimer’s disease.

The neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) is involved in amyloidogenesis, and the SORL1 gene is a major risk factor for Alzheimer’s disease (AD). We investigated AD-related CSF biomarkers for associations with SORL1 genetic variants in 105 German patients with mild cognitive impairment (MCI) and AD. The homozygous CC-allele of single nucleotide polymorphism (SNP) 4 was associated with increased Tau concentrations in AD, and the minor alleles of SNP8, SNP9, and SNP10 and the haplotype CGT of these SNPs were associated with increased SORL1 concentrations in MCI.

Cerebrospinal fluid BACE1 activity and brain amyloid load in Alzheimer's disease.

The secretase BACE1 is fundamentally involved in the development of cerebral amyloid pathology in Alzheimer's disease (AD). It has not been studied so far to what extent BACE1 activity in cerebrospinal fluid (CSF) mirrors in vivo amyloid load in AD. We explored associations between CSF BACE1 activity and fibrillar amyloid pathology as measured by carbon-11-labelled Pittsburgh Compound B positron emission tomography ([¹¹C]PIB PET).

Interrelations between CSF soluble AβPPβ, amyloid-β 1-42, SORL1, and tau levels in Alzheimer's disease.

Recently, light has been shed on possible interrelations between the two most important pathological hallmarks of Alzheimer's disease (AD): the amyloid cascade and axonal degeneration. In this study, we investigated associations between sβAPPβ, a product of the cleavage of the amyloid-β protein precursor (AβPP) by β-secretase, amyloid-β 1-42 (Aβ42), soluble SORL1 (also called LR11 or SORLA), a receptor that is involved in AβPP processing, and the marker of axonal degeneration tau in the cerebrospinal fluid (CSF) of 76 patients with mild cognitive impairment (MCI), 61 patients with AD, and 17 patients with frontotemporal dementia, which neuropathologically is not related to the amyloid pathology. In the AD group, significant associations between sAβPPβ, tau (p < 0.

Impact of SORL1 single nucleotide polymorphisms on Alzheimer's disease cerebrospinal fluid markers.

Background: Recently, genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) have emerged as risk factors for the development of Alzheimer's disease (AD).

Methods: In this study, SORL1 gene polymorphisms, which have been shown to be related to AD, were analyzed for associations with cerebrospinal fluid (CSF) amyloid beta1-42 (Aβ(1-42)), phosphorylated tau181, and total tau levels in a non-Hispanic Caucasian sample, which encompassed 100 cognitively healthy elderly individuals, 166 patients with mild cognitive impairment, and 87 patients with probable AD. The data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.

A simplified method to assess affinity of insulin autoantibodies.

Insulin autoantibodies (IAA) precede type 1 diabetes, but not all IAA-positive children develop other islet autoantibodies and disease. Diabetes risk can be stratified by laborious IAA affinity measurement using competition with multiple ligand concentrations. Here, we identify a single competitor concentration that discriminates low- and high-affinity IAA.

Tracing the Pathogenesis of Type 1 Diabetes: A Report on the 44th Annual Meeting of the European Association for the Study of Diabetes (EASD).

Clinical type 1 diabetes is preceded by autoimmune destruction of the pancreatic beta-cells. However, progression to disease is not uniform. One challenge facing current diabetes research is therefore to identify biomarker profiles that accurately reflect the individual stage of type 1 diabetes pathogenesis and develop new techniques to distinguish between these profiles and associated diabetes risks.

Expression of interleukin-16 by tumor-associated macrophages/activated microglia in high-grade astrocytic brain tumors.

Introduction: Macrophages/microglial cells are considered as immune cells in the central nervous system. Interleukin (IL)-16 is a proinflammatory cytokine produced by activated monocytic cells.

Materials And Methods: Expression of IL-16 was analyzed by immunohistochemistry in human astrocytic brain tumors and the rat C6 glioblastoma tumor model.

Acute but not chronic stimulation of glial cells in rat spinal cord by systemic injection of lipopolysaccharide is associated with hyperalgesia.

We have analyzed development of mechanical hyperalgesia after repeated systemic lipopolysaccharide (LPS) injections and correlated these findings with stimulation of astrocytes and microglia in spinal cord. Male Lewis rats received a single or seven intraperitoneal injections of LPS. Mechanical hyperalgesia was measured as rat hindpaw withdrawal thresholds (PWTs).

Combinations of TLR and NOD2 ligands stimulate rat microglial P2X4R expression.

As ATP-gated ion channels, P2X4 receptors (P2X4R) of microglial cells play a crucial role in central nervous system (CNS) inflammation. In this study, we used rat microglial cell cultures to examine P2X4R expression in response to stimulation by combination of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain 2 (NOD2) receptors. Various TLR1-9 ligands and NOD2 agonist muramyldipeptide (MDP) were investigated.

Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain.

P2X4 receptor (P2X4R) is an ion channel gated by adenosine 5'-triphosphate. Here we report the presence and the distribution of P2X4R in rat spinal cord by immunohistochemical analysis in an inflammatory pain model. Peripheral inflammation was induced by subcutaneous injection of 4% formalin into the rat hindpaw.

Binding and uptake of immunostimulatory CpG oligodeoxynucleotides by human neuroblastoma cells.

Oligodeoxynucleotides (ODNs) that contain unmethylated CpG dinucleotides (CpG-ODN) trigger a strong innate immune response in vertebrates. They have been used to eradicate experimental neuroblastoma, but a direct interaction of CpG-ODN with neuroblastoma cells has not been investigated. We have analyzed uptake, binding, and intracellular distribution of CpG-ODN in the neuroblastoma cells line SKNSH.

Expression of P2X4 receptor in rat C6 glioma by tumor-associated macrophages and activated microglia.

Here we report an immunohistochemical analysis of P2X4 receptor (P2X4R), an ATP-gated ion channel, expression in rat C6 glioma model. Striking P2X4R expression was detected in compact and infiltrative tumor growth areas. Expression of P2X4R by perivascular cells was observed in normal control brain and in brain areas not affected by tumor growth.

Expression of interleukin-16 by microglial cells in inflammatory, autoimmune, and degenerative lesions of the rat brain.

Here we report a comparative analysis of interleukin-16 (IL-16) expression by microglial cells of the normal rat brain in trimethyltin (TMT) neurotoxicity, experimental autoimmune uveitis (EAU), encephalomyelitis (EAE), and viral infection (Borna disease, Borna disease virus) by immunohistochemistry. Striking differences were observed. In contrast to the human brain, IL-16 was not expressed constitutively in the rat brain.