In vivo 1H-magnetic resonance spectroscopy can detect metabolic changes in APP/PS1 mice after donepezil treatment

<p>Abstract</p> <p>Background</p> <p>Donepezil improves cognitive functions in AD patients. Effects on the brain metabolites N-acetyl-L-aspartate, choline and <it>myo-</it>inositol levels have been reported in clinical studies using this drug. The APP/PS1 mouse coexpresses the mutated forms of human β-amyloid precursor protein (APP) and mutated human presenilin 1 (PS1). Consequently, the APP/PS1 mouse model reflects important features of the neurochemical profile in humans. <it>In vivo </it>magnetic resonance spectroscopy (¹H-MRS) was performed in fronto-parietal cortex and hippocampus (ctx/hipp) and in striatum (str). Metabolites were quantified using the LCModel and the final analysis was done using multivariate data analysis. The aim of this study was to investigate if multivariate data analysis could detect changes in the pattern of the metabolic profile after donepezil treatment.</p> <p>Results</p> <p>Significant differences were observed in the metabolic pattern of APP/PS1 mice in both str and ctx/hipp before and after donepezil treatment using multivariate data analysis, evidencing a significant treatment effect. A treatment effect was also seen in wild type (wt) mice in str. A significant decrease in the metabolic ratio taurine/creatine (Tau/tCr) was related to donepezil treatment (p < 0.05) in APP/PS1 mice in both brain regions. Furthermore, a significant influence on the choline/creatine (tCho/tCr) level was observed in treated APP/PS1 mice compared to untreated in str (p = 0.011). Finally, there was an increase in glutamate/creatine (Glu/tCr) in str in wt mice treated with donepezil.</p> <p>Conclusion</p> <p>Multivariate data analysis can detect changes in the metabolic profile in APP/PS1 mice after donepezil treatment. Effects on several metabolites that are measurable <it>in vivo </it>using MR spectroscopy were observed. Changes in Tau/tCr and tCho/tCr could possibly be related to changed cholinergic activity caused by donepezil treatment.</p

Kv1.1 null mice have enlarged hippocampus and ventral cortex

BACKGROUND: Mutations in the Shaker-like voltage-gated potassium channel Kv1.1 are known to cause episodic ataxia type 1 and temporal lobe epilepsy. Mice that express a malfunctional, truncated Kv1.1 (BALB/cByJ-Kv1.1(mceph/mceph)) show a markedly enlarged hippocampus and ventral cortex in adulthood. RESULTS: To determine if mice lacking Kv1.1 also develop a brain enlargement similar to mceph/mceph, we transferred Kv1.1 null alleles to the BALB/cByJ background. Hippocampus and ventral cortex was then studied using in vivo 3D-magnetic resonance imaging and volume segmentation in adult Kv1.1 null mice, BALB/cByJ-Kv1.1(mceph/mceph), BALB/cByJ-Kv1.1(mceph/+), BALB.C3HeB -Kv1.1(-/+ )and wild type littermates. The Kv1.1 null brains had dramatically enlarged hippocampus and ventral cortex. Mice heterozygous for either the null allele or the mceph allele had normal-sized hippocampus and ventral cortex. CONCLUSION: Total absence of Kv1.1 can induce excessive overgrowth of hippocampus and ventral cortex in mice with a BALB/cByJ background, while mice with one wild type Kv1.1 allele develop normal-sized brains

Scale setting for Nf=3+1N_f=3+1 QCD

We present the scale setting for a new set of gauge configurations generated with $N_f=3+1$ Wilson quarks with a non-perturbatively determined clover coefficient in a massive O($a$) improvement scheme. The three light quarks are degenerate, with the sum of their masses being equal to its value in nature and the charm quark has its physical mass. We use open boundary conditions in time direction to avoid the problem of topological freezing at small lattice spacings and twisted-mass reweighting for improved stability of the simulations. The decoupling of charm at low energy allows us to set the scale by measuring the value of the low-energy quantity $t_0^\star/a^2$, which is the flow scale $t_0$ at our mass point, and comparing it to an $N_f=2+1$ result in physical units. We present the details of the algorithmic setup and tuning procedure and give the bare parameters of ensembles with two lattice spacings a=0.054 fm and a=0.043 fm. We discuss finite volume effects and lattice artifacts and present physical results for the charmonium spectrum. In particular the hyperfine splitting between the $\eta_c$ and $J/\psi$ mesons agrees very well with its physical value.Comment: 25 pages, 9 figures. Version accepted for publication in the European Physical Journal

P3‐221: Plasma inflammatory markers correlate with severity in Alzheimer's disease

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Reliability of visual assessment of medial temporal lobe atrophy

Background: Medial temporal lobe atrophy (MTA) has been found to be an early sign of Alzheimer’s disease (AD). Visual assessment of MTA (vaMTA) is a rapid, cost-efficient and clinically adaptable visual interpretation method for rating MTA, based on coronal magnetic resonance imaging (MRI) scans. The method was developed by Scheltens et al in the 1990s. Purpose: The aim of this thesis was to investigate the reliability of vaMTA using the Scheltens rating scale: on a long-term basis, compared with volumetric calculation, compared with multivariate analyses and, finally, tested in a clinical situation. In Study I, MRI scans of 100 patients were visually assessed six times over a 1-year period. Two radiologists, with different backgrounds, performed the assessments independently of each other. The results showed a high degree of reproducibility when performed by an experienced investigator. The reproducibility drops when assessment is rarely performed. Study II was a comparison between vaMTA and measurement of hippocampal volume in 544 non-demented elderly individuals from the SwedishNational Study of Ageing and Care in Kungsholmen (SNAC-K). A significant correlation was found between the two methods. Cut-off values for MTA scores in normal ageing were also suggested. In Study III the reliability of Scheltens’ visual assessment rating scale for assessing MTA was compared with that of a multivariate MRI classification method, orthogonal projections to latent structures (OPLS), and manually measured hippocampal volumes to distinguish between subjects with AD and healthy elderly controls (CTL). A comparison between the different techniques was also performed in predicting future developments from mild cognitive impairment (MCI) to AD. The prediction accuracies in distinguishing between AD patients and CTL were high for all three modalities. All three methods were also highly accurate in identifying subjects who converted from MCI to AD at 1-year follow-up. Finally, in Study IV, vaMTA scores were used in a validation study of the proposed new “Dubois criteria” in Alzheimer’s disease, in which MTA is one of four important biomarkers. A retrospective study of 150 patients was carried out to compare the traditional diagnostic criteria for dementia with the new criteria suggested by Dubois et al. The results showed a lack of accuracy for the new AD criteria, as they were valid for only 55% of the clinically diagnosed patients with full-blown AD in this study. Conclusion: Visual assessment of MTA using the MTA scale is reliable when performed on a daily basis. Medial temporal lobe atrophy scores have a significant correlation to hippocampal volume measurements, can predict conversion from MCI to AD with similar accuracy as can volumetric calculations and multivariate analysis, and can be used as supportive biomarker in the work-up of AD

Differential Associations of IL-4 With Hippocampal Subfields in Mild Cognitive Impairment and Alzheimer’s Disease

Background/Aims: We aimed to assess the association between in volumetric measures of hippocampal sub-regions – in healthy older controls (HC), subjects with mild cognitive impairment (MCI) and AD- with circulating levels of IL-4.Methods: From AddNeuroMed Project 113 HC, 101 stable MCI (sMCI), 22 converter MCI (cMCI) and 119 AD were included. Hippocampal subfield volumes were analyzed using Freesurfer 6.0.0 on high-resolution sagittal 3D-T1W MP-RAGE acquisitions. Plasmatic IL-4 was measured using ELISA assay.Results: IL-4 was found to be (a) positively associate with left subiculum volume (β = 0.226, p = 0.037) in sMCI and (b) negatively associate with left subiculum volume (β = -0.253, p = 0.011) and left presubiculum volume (β = -0.257, p = 0.011) in AD.Conclusion: Our results indicate a potential neuroprotective effect of IL-4 on the areas of the hippocampus more vulnerable to aging and neurodegeneration

Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease

Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods—quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, γ-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis