Journal of Alzheimer's disease : JAD
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Comparative Study
Comparison of xMAP and ELISA assays for detecting cerebrospinal fluid biomarkers of Alzheimer's disease.
The best-studied biomarkers of Alzheimer's disease (AD) are the pathologically-linked cerebrospinal fluid (CSF) proteins amyloid-β 42 (Aβ(1-42)), total tau (t-tau), and tau phosphorylated on amino acid 181 (p-tau(181)). Many laboratories measure these proteins using enzyme-linked immunosorbent assay (ELISA). Multiplex xMAP Luminex is a semi-automated assay platform with reduced intra-sample variance, which could facilitate its use in CLIA-approved clinical laboratories. ⋯ Log-transformation of ELISA and xMAP levels made the variance constant in all three biomarkers and improved the linear regression: t-tau concentrations were highly correlated (r = 0.94); p-tau(181) concentrations by ELISA can be better predicted using both the t-tau and p-tau(181) xMAP values (r = 0.96) as compared to p-tau(181) concentrations alone (r = 0.82); correlation of Aβ(1-42) concentrations was relatively weaker but still high (r = 0.77). Among all six protein/assay combinations, xMAP Aβ(1-42) had the best accuracy for diagnostic classification (88%) between AD and control subjects. In conclusion, our study demonstrates that multiplex xMAP is an appropriate assay platform providing results that can be correlated with research-based ELISA values, facilitating the incorporation of this diagnostic biomarker into routine clinical practice.
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The structural integrity of the cerebral white matter, including that of the white matter lesions (WML) and of the surrounding normal appearing white matter (NAWM), can be assessed with diffusion tensor imaging (DTI), which is suggested to be of added value in the explanation of cognitive dysfunction in cerebral small vessel disease (SVD). We investigated the value of DTI of NAWM and WML in addition to conventional magnetic resonance imaging (MRI) parameters in the variance of cognitive performance in subjects with SVD. 499 individuals with SVD, 50-85 years, without dementia, underwent MRI scanning, including a DTI sequence. Grey matter, white matter (WM), and WML volume, number of microbleeds, lacunar and territorial infracts, and mean diffusivity (MD) and fractional anisotropy (FA) in NAWM, WML, and total WM were related to cognitive performance in multivariate regression analyses, after adjustment for age, gender, and education. ⋯ Both mean MD and FA of the NAWM, WML, and total WM did not substantially contribute to the explained variance of cognitive function, to that already explained by conventional MRI parameters. When considered separately, the MD of the (NA)WM had the strongest association with cognitive performance. In conclusion, DTI of NAWM and WML has limited additional value to conventional MRI parameters in the etiological explanation of the variance in cognitive function among individuals with SVD.
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The aim of this work was to explore the applicable value of (1)H-MRS evaluation on the treatment of Alzheimer's disease (AD) with neural stem cell (NSC) transplantation by quantitative analysis of metabolite changes in the hippocampal area in AβPP/PS1 transgenic (tg) mice. The tg mice (n = 30) aged 12 months were randomized into two subgroups: One receiving NSCs and the other receiving PBS transplantation in the bilateral hippocampal CA1 region. The wild-type mice (n = 15) were used as the control group. (1)H-MRS was performed before transplantation and 6 weeks after transplantation to measure the change of N-acetylaspartate (NAA), myo-inositol (mI), glutamate (Glu), choline (Cho), and creatine (Cr) in the hippocampus. ⋯ Histology showed the number of neurons in the hippocampal CA1 region increased significantly in the NSC group than those in the PBS group (p < 0.05), and the number of astrocytes significantly decreased in the NSC group compared with the PBS group. Ultrastructure showed that the neurons in the NSC group were morphologically normal. In conclusion, (1)H-MRS can display intracranial metabolite changes before and after NSC transplantation in tg mice and has a applicable value in evaluating the therapeutic effect of NSCs on AD.
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The output of cortical pyramidal cells reflects the balance between excitatory inputs of cortical and subcortical origin, and inhibitory inputs from distinct populations of cortical GABAergic interneurons, each of which selectively innervate different domains of neuronal pyramidal cells (i.e., dendrites, soma and axon initial segment [AIS]). In Alzheimer's disease (AD), the presence of amyloid-β (Aβ) plaques alters the synaptic input to pyramidal cells in a number of ways. However, the effects of Aβ plaques on the AIS have still not been investigated to date. ⋯ In the AβPP/PS1 transgenic mouse model of AD, we have investigated the effects of Aβ plaques on the morphological and neurochemical features of the AIS, including the cisternal organelle, using immunocytochemistry and confocal microscopy, as well as studying the innervation of the AIS by chandelier cell axon terminals. There is a strong reduction in GABAergic terminals that appose AIS membrane surfaces that are in contact with Aβ plaques, indicating altered inhibitory synapsis at the AIS. Thus, despite a lack of gross structural alterations in the AIS, this decrease in GABAergic innervation may deregulate AIS activity and contribute to the hyperactivity of neurons in contact with Aβ plaques.
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Iron abnormalities are observed in the brains of Alzheimer's disease (AD) patients, but it is unclear whether common disorders of systemic iron overload such as hemochromatosis alter risks of AD. We used microarrays and real-time reverse transcription-PCR to investigate changes in the brain transcriptome of adult Hfe-/- mice, a model of hemochromatosis, relative to age- and gender-matched wildtype controls. Classification by functional pathway analysis revealed transcript changes for various genes important in AD. ⋯ The effects appeared relatively specific for AD in that few genes pertaining to other important neurodegenerative diseases, notably Parkinson's disease and Huntington's disease, or to inflammation, oxidative stress, or apoptosis, showed altered transcript levels. The observed effects on AD-related gene transcripts do not appear to be consistent with increased AD risk in HFE hemochromatosis and might, if anything, be predicted to protect against AD to some extent. As Hfe-/- mice did not have higher brain iron levels than wildtype controls, these studies highlight the need for further research in models of more severe hemochromatosis with brain iron loading.