Regional brain activity after prolonged cholinergic enhancement in early Alzheimer's disease

This functional magnetic resonance imaging (fMRI) study examined changes in brain activation after prolonged (20 weeks) and stabilized treatment with the cholinesterase inhibitor galantamine in a small group of patients with very mild Alzheimer's disease (AD). Two cognitive activation paradigms were chosen: one requiring semantic association and the other relying on attention and requiring target detection. A group of age- and education-matched healthy controls was also scanned for comparison. A modest (but not statistically significant) improvement in behavioral scores after treatment was observed in both fMRI tasks. There were brain activation increases in the semantic association task after treatment, and the differences in brain activation present in the comparison of AD patients' baseline images with those of controls were not detectable after treatment. In the target detection task, regions that were activated in the elderly controls but not in the baseline images of the AD group also showed significant activation after treatment. Overall, however, the increases were modest and might reflect the heterogeneity of clinical response to treatment in this small group. Future pharmacological fMRI studies should include clinical response as a factor in the analysis of cholinergic enhancement effects in AD patients.     

Magnetic resonance elastography of the brain in a mouse model of Alzheimer's disease: initial results

The increasing prevalence of Alzheimer's disease (AD) has provided motivation for developing novel methods for assessing the disease and the effects of potential treatments. Magnetic resonance elastography (MRE) is an MRI-based method for quantitatively imaging the shear tissue stiffness in vivo. The objective of this research was to determine whether this new imaging biomarker has potential for characterizing neurodegenerative disease. Methods were developed and tested for applying MRE to evaluate the mouse brain, using a conventional large bore 3.0T MRI system. The technique was then applied to study APP-PS1 mice, a well-characterized model of AD. Five APP-PS1 mice and 8 age-matched wild-type mice were imaged immediately following sacrifice. Brain shear stiffness measurements in APP-PS1 mice averaged 22.5% lower than those for wild-type mice (P = .0031). The results indicate that mouse brain MRE is feasible at 3.0T, and brain shear stiffness has merit for further investigation as a potential new biomarker for Alzheimer's disease.     

A 1H MRS study of probable Alzheimer's disease and normal aging: implications for longitudinal monitoring of dementia progression

In order to evaluate the capability of 1H MRS to monitor longitudinal changes in subjects with probable Alzheimer's disease (AD), the temporal stability of the metabolite measures N-acetylaspartate and N-acetylaspartylglutamate (NA), total Creatine (Cr), myo-Inositol (mI), total Choline (Chol), NA/Cr, mI/Cr, Chol/Cr and NA/mI were investigated in a cohort of normal older adults. Only the metabolite measures NA, mI, Cr, NA/Cr, mI/Cr, and NA/mI were found to be stable after a mean interval of 260 days. Relative and absolute metabolite measures from a cohort of patients with probable AD were subsequently compared with data from a sample of normal older adult control subjects, and correlated with mental status and the degree of atrophy in the localized voxel. Concentrations of NA, NA/Cr, and NA/mI were significantly reduced in the AD group with concomitant significant increases in mI and mI/Cr. There were no differences between the two groups in measures of Cr, Chol, or Chol/Cr. Significant correlations between mental status as measured by the Mini-Mental State Examination and NA/mI, mI/Cr and NA were found. These metabolite measures were also significantly correlated with the extent of atrophy (as measured by CSF and GM composition) in the spectroscopy voxel.     

Diffusion abnormality in the posterior cingulum and hippocampal volume: correlation with disease progression in Alzheimer's disease

The purpose of this study was to determine correlations among disease progression, diffusion abnormalities in the posterior cingulum and hippocampal volume in patients with Alzheimer's disease (AD). We studied 25 AD patients by neuropsychological testing, including the Mini-Mental State Examination (MMSE), and by magnetic resonance imaging, including diffusion tensor imaging (DTI) and high-resolution three-dimensional T1-weighted imaging. The MMSE score was used as an indicator of disease progression. Diffusion tensor tractography of the posterior cingulum was generated from the DTI; mean diffusivity (MD) and fractional anisotropy (FA) were measured in co-registered voxels along the posterior cingulum. Hippocampal volume was measured using automated voxel-based morphometry. The relationships among MMSE score, hippocampal volume and MD and FA of the posterior cingulum were evaluated by bivariate correlation analysis. MD in the posterior cingulum correlated significantly with the MMSE score. No significant correlation was seen between FA and MMSE score and between hippocampal volume and MMSE score, FA or MD. Our results suggest that MD in the posterior cingulum is a more sensitive indicator of progression of AD than FA of the posterior cingulum and hippocampal volume.     

Reduced field-of-view diffusion-weighted imaging of the brain at 7 T

Ventral and rostral regions of the brain are of emerging importance for the MRI characterization of early dementia, traumatic brain injury and epilepsy. Unfortunately, standard single-shot echo planar diffusion-weighted imaging of these regions at high fields is contaminated by severe imaging artifacts in the vicinity of air–tissue interfaces. To mitigate these artifacts and improve visualization of the temporal and frontal lobes at 7 T, we applied a reduced field-of-view strategy, enabled by outer volume suppression (OVS) with novel quadratic phase radiofrequency (RF) pulses, combined with partial Fourier and parallel imaging methods. The new acquisition greatly reduced the level of artifacts in six human subjects (including four patients with early symptoms of dementia).     

The phase shift index for marking functional asynchrony in Alzheimer's disease patients using fMRI

Our previous study suggested that the functional magnetic resonance imaging MRI (fMRI) COSLOF Index (CI) could be used as a quantitative biomarker for Alzheimer's disease (AD). The fMRI CI was lowest in the AD group (0.13+/-0.10), followed by the mild cognitive impairment (MCI) group (0.20+/-0.05) and the control group (0.34+/-0.09). The current study continues an investigation into which of the following two factors has a dominant role in determining the CI: the signal-to-noise ratio (SNR) or the phase shift of spontaneous low-frequency (SLF) components. By using a theoretical model for SLF components, we demonstrated that the normalized CI does not depend on the SNR of the SLF components. Further analysis shows that by taking the ratio of the cross-correlation coefficient to the maximum-shifted cross-correlation coefficient, the SNR factor can be canceled. Therefore, the determination of the phase shift index (PSI) method is independent of the SNR, and the PSI provides an accurate measure of the phase shift between SLF components. By applying this PSI method to the control, MCI and AD groups of subjects, experimental results demonstrated that the PSI was highest in the AD group (72.6+/-11.3 degrees ), followed by the MCI group (58.6+/-5.7 degrees ) and, finally, the control group (40.6+/-8.4 degrees ). These results suggest that the larger is the PSI value, the more asynchrony exists between SLF components.     

Immunohistological detection of <Emphasis Type="Italic">Chlamydia pneumoniae</Emphasis> in the Alzheimer's disease brain

Background  

Sporadic late-onset Alzheimer's disease (AD) appears to evolve from an interplay between genetic and environmental factors. One environmental factor that continues to be of great interest is that of Chlamydia pneumoniae infection and its association with late-onset disease. Detection of this organism in clinical and autopsy samples has proved challenging using a variety of molecular and histological techniques. Our current investigation utilized immunohistochemistry with a battery of commercially available anti-C. pneumoniae antibodies to determine whether C. pneumoniae was present in areas typically associated with AD neuropathology from 5 AD and 5 non-AD control brains.     

Characterization of BOLD-fMRI signal during a verbal fluency paradigm in patients with intracerebral tumors affecting the frontal lobe

Previous studies have indicated that the BOLD-fMRI signal can be modified by tumor processes in close vicinity to functional brain areas. This effect has been investigated primarily for the perirolandic area but there is only a limited number of studies concerning frontal cortical regions. Therefore, the aim of the current study was to characterize BOLD-fMRI signal and activation patterns in patients with frontal brain tumors while performing a verbal fluency task. Six patients (ages 31-56 years) suffering from frontal (5 left sided and 1 right sided) intracerebral tumors were examined with fMRI while performing a verbal fluency task in a blocked paradigm design. Eight healthy volunteers served as the control group. The patients (5 right and 1 left handed) demonstrated left frontal activation which could be clearly located outside the tumor area and adjacent edema with varying degrees of additional right frontal activation. In the predominant left frontal activation cluster, the mean voxel based z-score and cluster size were not statistically different between patients and controls. The present fMRI study is indicating that language related BOLD signal changes in the frontal cortex of patients with tumors close to functional areas were comparable to the signal in normal controls. Additionally, the temporal hemodynamic response characteristic was comparable in both groups. This is an important finding consistent with PET results and corroborates the feasibility of functional mapping approaches in patients with tumors affecting the frontal lobe. Additional studies investigating alterations of the hemodynamic response depending on tumor location and histology are required in order to further elucidate the association between pathophysiology and BOLD fMRI signal.     

Increased glucose concentration in the hippocampus in early Alzheimer's disease following oral glucose ingestion

Glucose is the primary source of energy for brain cells. Because energy storage in the brain is limited, an uninterrupted supply of glucose and its rapid metabolism are essential for normal cognitive function. This study utilized an oral glucose load to examine hippocampal glucose metabolism in early Alzheimer's disease (AD) - a disease characterized by progressive deterioration of cognitive function and glucose hypometabolism. Short echo time 1H MR spectra (20 ms) from the right hippocampus of 8 patients with probable AD, 14 healthy elderly and 14 healthy young adults were compared pre- and post-glucose loading. In contrast to the healthy adults, the AD patients exhibited significantly elevated hippocampal glucose concentrations post-glucose ingestion relative to baseline (P < .01). These results suggest that cerebral glucose hypometabolism in AD leads to an increased steady-state concentration of cerebral glucose. This research demonstrates the feasibility of studying cerebral glucose metabolism in AD with 1H MR spectroscopy.     

Pharmacophore mapping of the crucial mediators of acetylcholinesterase and butyrylcholinesterase dual inhibition in Alzheimer's disease

Optimization and re-optimization of bioactive molecules using in silico methods have found application in the design of more active ones. Herein, we applied a pharmacophore modeling approach to screen potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) aimed at Alzheimer's disease (AD) treatment. The investigation entails molecular dynamics simulation, docking, pharmacophore modeling, drug-like screening, and binding energy analysis. We prepared a pharmacophore model from approved inhibitors of AChE and BuChE to predict the crucial moieties required for optimum molecular interaction with these proteins. The obtained pharmacophore model, used for database screening via some critical criteria, showed 229 hit molecules. Further analyses showed 42 likely dual inhibitors of AChE/BuChE with drug-like and pharmacokinetics properties the same as the approved cholinesterase inhibitors. Finally, we identified 14 dual molecules with improved potentials over the existing inhibitors and simulated ZINC92385797 bound to human AChE and BuChE structure after noticing that these 14 molecules are similar. The selected compound maintained relative stability at the active sites of both proteins over 120 ns simulation. Our integrated protocols showed the pertinent recipes of anti-AD drug design through the in silico pipeline.

Graphical abstract

     

The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease.     

Aerodynamic measurements of patients with parkinson''s disease

Patients with Parkinson's disease commonly complain of voice dysfunction. Most of these complaints can be attributed to the known muscular control disorders that occur with Parkinson's disease. However, the manifestations of Parkinson's disease muscular dysfunction on parameters of phonation such as airflow, laryngeal resistance, and subglottal pressure necessary to sustain phonation have not been reported. The purpose of this study was to examine the aerodynamic characteristics of flow, laryngeal resistance, and phonation pressure threshold in a heterogeneous population of patients with Parkinson's disease who had varying voice complaints and to compare the data to similar studies for human subjects who have no voice complaints. The studies used a noninvasive method of detecting flow and acoustic signal from the lips, oral cavity and nose during phonation and used an external flow interruption technique to estimate subglottal pressure and phonation threshold pressure. About one third of the patients could not produce phonation at regular and loud intensities that were comfortable for normal subjects. The mean subglottal pressure (SGP) of patients with Parkinson disease who could produce 3 levels of intensity comparable to normal subjects was significantly higher than the mean SG-Ps for normal subjects for the same intensities of vocal production. The mean flow rates measured from patients with Parkinson's disease at the same 3 intensities of phonation was not significantly greater than in normal subjects. This indicated that the mean laryngeal resistance calculated for patients with Parkinson's disease was notably and significantly greater than mean laryngeal resistance calculated for normal subjects at the same intensity levels. The mean vocal efficiency (VE) for normal subjects was not significantly different than the mean VE for patients with Parkinson's disease, because greater pressure was used to generate similar flow and acoustic energy. These findings correlate with the perception of patients with Parkinson's disease that they are working harder to produce phonation. The observation of notably greater laryngeal resistance and phonation threshold pressure in patients with Parkinson's disease suggests that further studies of the glottic aperture in patients with Parkinson' disease may be useful for understanding how this common motor disorder disturbs phonation.     

MR image-based measurement of rates of change in volumes of brain structures. Part II: application to a study of Alzheimer's disease and normal aging

We present global and regional rates of brain atrophy measured on serially acquired T1-weighted brain MR images for a group of Alzheimer's disease (AD) patients and age-matched normal control (NC) subjects using the analysis procedure described in Part I. Three rates of brain atrophy: the rate of atrophy in the cerebrum, the rate of lateral ventricular enlargement and the rate of atrophy in the region of temporal lobes, were evaluated for 14 AD patients and 14 age-matched NC subjects. All three rates showed significant differences between the two groups. However, the greatest separation of the two groups was obtained when the regional rates were combined. This application has demonstrated that rates of brain atrophy, especially in specific regions of the brain, based on MR images can provide sensitive measures for evaluating the progression of AD. These measures will be useful for the evaluation of therapeutic effects of novel therapies for AD.     

Downstream targets of methyl CpG binding protein 2 and their abnormal expression in the frontal cortex of the human Rett syndrome brain

Background  

The Rett Syndrome (RTT) brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected.     

In vivo magnetic resonance diffusion measurement in the brain of patients with multiple sclerosis.

Measurement of water self-diffusion in the brain in 25 patients with multiple sclerosis was performed by magnetic resonance imaging. Quantitative diffusion measurements were obtained using single spin-echo pulse sequences with pulsed magnetic field gradients of different magnitude. Twenty-two of these patients also underwent measurement of the transverse relaxation time (T2). Only one plaque was evaluated in each patient. Based on prior knowledge, 12 plaques were classified as being 3 mo or less in age, and 7 plaques were classified as being more than 3 mo old. In all 25 plaques, water self-diffusion was found to be higher than in apparently normal white matter. Furthermore, water self-diffusion was found to be higher in acute plaques compared with chronic plaques. Finally, a slight tendency toward a relationship between the diffusion capability and T2 was found. We believe that an increased diffusion capability signifies an increase of the extracellular water space, which probably is related to the degree of demyelination. Thus, measurement of water self-diffusion in multiple sclerosis plaques may contribute to the study of pathogenesis of demyelination.     

Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants

Background  

Amyloid precursor protein (APP) is enzymatically cleaved by γ-secretase to form two peptide products, either Aβ40 or the more neurotoxic Aβ42. The Aβ42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.     

Optimizing brain MRI protocols in the follow-up of patients with multiple sclerosis T2-weighted MRI of the brain after the administration of gadopentetate dimeglumine

The aim of our study was to determine whether T2-weighted (T2w) MRI of the brain could be performed immediately after the administration of gadopentetate dimeglumine (gadolinium DTPA) in patients with multiple sclerosis (MS) without a loss in image quality or diagnostic reliability. Sixteen patients with clinically diagnosed MS were included in the study. Twenty-four patients with various cerebral pathologies (14 patients with multiple lacunar lesions) were examined in order to exclude masking of T2 hyperintense lesions other than MS lesions. Images of 10 patients without pathological changes served as a control condition for the qualitative analysis. In these 50 patients, T1w and T2w MRI was performed before and after the administration of gadolinium DTPA. Signal intensities were measured within T2 hyperintense cerebral lesions, in T1-enhancing lesions and in normal appearing brain tissue on T2w turbo spin-echo (TSE) sequences. Both quantitative and qualitative analysis did not show significant differences between T2w pre- and postcontrast series. T2w MRI performed prior to and after the administration of gadolinium DTPA provides similar information in patients with MS. With a TR of 3.2 s, not a single lesion was obscured on T2w postcontrast series. Acquisition of T2w MR images immediately after the administration of gadolinium DTPA allows for shorter examination time and assures sufficient time for contrast enhancement in cerebral lesions with a disrupted blood-brain barrier.     

Diffusion MRI detects basal forebrain cholinergic abnormalities in the 3xTg-AD mouse model of Alzheimer's disease

Degeneration of the basal forebrain (BF) is detected early in the course of Alzheimer's disease (AD). Reduction in the number of BF cholinergic (ChAT) neurons associated with age-related hippocampal cholinergic neuritic dystrophy is described in the 3xTg-AD mouse model; however, no prior diffusion MRI (dMRI) study has explored the presence of BF alterations in this model. Here we investigated the ability of diffusion MRI (dMRI) to detect abnormalities in BF microstructure for the 3xTg-AD mouse model, along with related pathology in the hippocampus (HP) and white matter (WM) tracks comprising the septo-hippocampal pathway. 3xTg-AD and normal control (NC) mice were imaged in vivo using the specific dMRI technique known as diffusional kurtosis imaging (DKI) at 2, 8, and 15 months of age, and 8 dMRI parameters were measured at each time point. Our results revealed significant lower dMRI values in the BF of 2 months-old 3xTg-AD mice compared with NC mice, most likely related to the increased number of ChAT neurons seen in this AD mouse model at this age. They also showed significant age-related dMRI changes in the BF of both groups between 2 and 8 months of age, mainly a decrease in fractional anisotropy and axial diffusivity, and an increase in radial kurtosis. These dMRI changes in the BF may be reflecting the complex aging and pathological microstructural changes described in this region. Group differences and age-related changes were also observed in the HP, fimbria (Fi) and fornix (Fx). In the HP, diffusivity values were significantly higher in the 2 months-old 3xTg-AD mice, and the HP of NC mice showed a significant increase in axial kurtosis after 8 months, reflecting a normal pattern of increased fiber density complexity, which was not seen in the 3xTg-AD mice. In the Fi, mean and radial diffusivity values were significantly higher, and fractional anisotropy, radial kurtosis and kurtosis fractional anisotropy were significantly lower in the 2 months-old 3xTg-AD mice. The age trajectories for both NC and TG mice in the Fi and Fx were similar between 2 and 8 months, but after 8 months there was a significant decrease in diffusivity metrics associated with an increase in kurtosis metrics in the 3xTg-AD mice. These later HP, Fi and Fx dMRI changes probably reflect the growing number of dystrophic neurites and AD pathology progression in the HP, accompanied by WM disruption in the septo-hippocampal pathway. Our results demonstrate that dMRI can detect early cytoarchitectural abnormalities in the BF, as well as related aging and neurodegenerative changes in the HP, Fi and Fx of the 3xTg-AD mice. Since DKI is widely available on clinical scanners, these results also support the potential of the considered dMRI parameters as in vivo biomarkers for AD disease progression.     

Individual identification using multi-metric of DTI in Alzheimer's disease and mild cognitive impairment

Accurate identification of Alzheimer's disease(AD) and mild cognitive impairment(MCI) is crucial so as to improve diagnosis techniques and to better understand the neurodegenerative process. In this work, we aim to apply the machine learning method to individual identification and identify the discriminate features associated with AD and MCI. Diffusion tensor imaging scans of 48 patients with AD, 39 patients with late MCI, 75 patients with early MCI, and 51 age-matched healthy controls(HCs) are acquired from the Alzheimer's Disease Neuroimaging Initiative database. In addition to the common fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity metrics, there are two novel metrics,named local diffusion homogeneity that used Spearman's rank correlation coefficient and Kendall's coefficient concordance,which are taken as classification metrics. The recursive feature elimination method for support vector machine(SVM)and logistic regression(LR) combined with leave-one-out cross validation are applied to determine the optimal feature dimensions. Then the SVM and LR methods perform the classification process and compare the classification performance.The results show that not only can the multi-type combined metrics obtain higher accuracy than the single metric, but also the SVM classifier with multi-type combined metrics has better classification performance than the LR classifier.Statistically, the average accuracy of the combined metric is more than 92% for all between-group comparisons of SVM classifier. In addition to the high recognition rate, significant differences are found in the statistical analysis of cognitive scores between groups. We further execute the permutation test, receiver operating characteristic curves, and area under the curve to validate the robustness of the classifiers, and indicate that the SVM classifier is more stable and efficient than the LR classifier. Finally, the uncinated fasciculus, cingulum, corpus callosum, corona radiate, external capsule, and internal capsule have been regarded as the most important white matter tracts to identify AD, MCI, and HC. Our findings reveal a guidance role for machine-learning based image analysis on clinical diagnosis.     

Transient dynamics in motor control of patients with Parkinson's disease

Experimental observations of movement disorders including tremor and voluntary microdisplacements recorded in patients with Parkinson's disease (PD) during a simple visuomotor tracking task are analyzed. The performance of patients with PD having a very large amplitude tremor is characterized either by the intermittent appearance of transient dynamics or by the presence of sudden transitions in the amplitude or frequency of the signal. The need to develop new tools to characterize changes in dynamics (i.e., transitions) and to redefine neurological degeneration, such as Parkinson's disease, in terms of qualitative changes in oscillatory behaviors is emphasized.