ABSTRACT
Despite the enormous public health impact of Alzheimer's disease (AD), no disease-modifying treatment has yet been proven to be efficacious in humans. A rate-limiting step in the discovery of potential therapies for humans is the absence of efficient non-invasive methods of evaluating drugs in animal models of disease. Magnetic resonance spectroscopy (MRS) provides a non-invasive way to evaluate the animals at baseline, at the end of treatment, and serially to better understand treatment effects. In this study, MRS was assessed as potential outcome measure for detecting disease modification in a transgenic mouse model of AD. Passive immunization with two different antibodies, which have been previously shown to reduce plaque accumulation in transgenic AD mice, was used as intervention. Treatment effects were detected by MRS, and the most striking finding was attenuation of myo-inositol (mIns) increases in APP-PS1 mice with both treatments. Additionally, a dose-dependent effect was observed with one of the treatments for mIns. MRS appears to be a valid in vivo measure of anti-Aß therapeutic efficacy in pre-clinical studies. Because it is noninvasive, and can detect treatment effects, use of MRS-based endpoints could substantially accelerate drug discovery.
Subject(s)
Alzheimer Disease , Aspartic Acid/analogs & derivatives , Brain/metabolism , Immunization, Passive/methods , Magnetic Resonance Spectroscopy , Alzheimer Disease/genetics , Alzheimer Disease/immunology , Alzheimer Disease/therapy , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Aspartic Acid/metabolism , Choline , Disease Models, Animal , Humans , Inositol , Magnetic Resonance Imaging , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Peptide Fragments/metabolism , Presenilin-1/genetics , Statistics, NonparametricABSTRACT
Our laboratory and others have reported the ability to detect individual Alzheimer's disease (AD) amyloid plaques in transgenic mouse brain in vivo by magnetic resonance imaging (MRI). Since amyloid plaques contain iron, most MRI studies attempting to detect plaques in AD transgenic mouse brain have employed techniques that exploit the paramagnetic effect of iron and have had mixed results. In the present study, using five-way anatomic spatial coregistration of MR images with three different histological techniques, properties of amyloid plaques in AD transgenic mouse brain were revealed that may explain their variable visibility in gradient- and spin-echo MR images. The results demonstrate differences in the visibility of plaques in the cortex and hippocampus, compared to plaques in the thalamus, by the different MRI sequences. All plaques were equally detectable by T(2)SE, while only thalamic plaques were reliably detectable by T(2)*GE pulse sequences. Histology revealed that cortical/hippocampal plaques have low levels of iron while thalamic plaques have very high levels. However, the paramagnetic effect of iron does not appear to be the sole factor leading to the rapid decay of transverse magnetization (short T(2)) in cortical/hippocampal plaques. Accordingly, MRI methods that rely less on iron magnetic susceptibility effect may be more successful for eventual human AD plaque MR imaging, particularly since human AD plaques more closely resemble the cortical and hippocampal plaques of AD transgenic mice than thalamic plaques.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , Plaque, Amyloid/pathology , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/genetics , Animals , Cerebral Cortex/anatomy & histology , Cerebral Cortex/pathology , Hippocampus/anatomy & histology , Hippocampus/pathology , Humans , Iron/metabolism , Magnetic Resonance Imaging/methods , Mice , Mice, Transgenic , Organ Specificity , Thalamus/anatomy & histology , Thalamus/pathologyABSTRACT
The authors present the surgical technique and early results after 14 wedge "minus" osteotomies and 5 wedge "plus" osteotomies performed in 16 (age ranging from 45 to 71 years) patients with osteoarthritis of the knee. Use of the DERO system for external stabilization of the knee allows early mobilization of the joint. According to the HSS scale in 15 cases (18 knees) a good result was achieved. Self-assessment of the results of treatment by the patients w\yielded good results in 12 cases and satisfactory in 3. All patients report greater ease of ambulation on flat terrain, across stairs, an increase in ROM and a decrease of pain symptoms. In one case a bad result was caused by infection of the surgical wound. In the observed group no infections, no reaction d\around the pins nor loosening of the bars was noted.
