Michael Ewers

Automated detection of brain atrophy patterns based on MRI for the prediction of Alzheimer's disease

Subjects with mild cognitive impairment (MCI) have an increased risk to develop Alzheimers disease (AD). Voxel-based MRI studies have demonstrated that widely distributed cortical and subcortical brain areas show atrophic changes in MCI, preceding the onset of AD-type dementia. Here we developed a novel data mining framework in combination with three different classifiers including support vector machine (SVM), Bayes statistics, and voting feature intervals (VFI) to derive a quantitative index of pattern matching for the prediction of the conversion from MCI to AD. MRI was collected in 32 AD patients, 24 MCI subjects and 18 healthy controls (HC). Nine out of 24 MCI subjects converted to AD after an average follow-up interval of 2.5 years. Using feature selection algorithms, brain regions showing the highest accuracy for the discrimination between AD and HC were identified, reaching a classification accuracy of up to 92%. The extracted AD clusters were used as a search region to extract those brain areas that are predictive of conversion to AD within MCI subjects. The most predictive brain areas included the anterior cingulate gyrus and orbitofrontal cortex. The best prediction accuracy, which was cross-validated via train-and-test, was 75% for the prediction of the conversion from MCI to AD. The present results suggest that novel multivariate methods of pattern matching reach a clinically relevant accuracy for the a priori prediction of the progression from MCI to AD.

Assessing neuronal networks: Understanding Alzheimer's disease

Findings derived from neuroimaging of the structural and functional organization of the human brain have led to the widely supported hypothesis that neuronal networks of temporally coordinated brain activity across different regional brain structures underpin cognitive function. Failure of integration within a network leads to cognitive dysfunction. The current discussion on Alzheimers disease (AD) argues that it presents in part a disconnection syndrome. Studies using functional magnetic resonance imaging, positron emission tomography and electroencephalography demonstrate that synchronicity of brain activity is altered in AD and correlates with cognitive deficits. Moreover, recent advances in diffusion tensor imaging have made it possible to track axonal projections across the brain, revealing substantial regional impairment in fiber-tract integrity in AD. Accumulating evidence points towards a network breakdown reflecting disconnection at both the structural and functional system level. The exact relationship among these multiple mechanistic variables and their contribution to cognitive alterations and ultimately decline is yet unknown. Focused research efforts aimed at the integration of both function and structure hold great promise not only in improving our understanding of cognition but also of its characteristic progressive metamorphosis in complex chronic neurodegenerative disorders such as AD.

Multicentre variability of MRI-based medial temporal lobe volumetry in Alzheimer's disease

Magnetic resonance imaging (MRI)-based volumetry of medial temporal lobe regions is among the best established biomarker candidates of Alzheimers disease (AD) to date. This study assessed the effect of multicentre variability of MRI-based hippocampus and amygdala volumetry on the discrimination between patients with Alzheimers disease (AD) and mild cognitive impairment (MCI) and on the association of morphological changes with ApoE4 genotype and cognition. We studied 113 patients with clinically probable AD and 150 patients with amnestic MCI using high-resolution MRI scans obtained at 12 clinical sites. We determined effect sizes of group discrimination and random effects linear models, considering multicentre variability. Hippocampus and amygdala volumes were significantly reduced in AD compared with MCI patients using data pooled across centres. Multicentre variability did not significantly affect the power to detect a volume difference between AD and MCI patients. Among cognitive measures, delayed recall of verbal and non-verbal material was significantly correlated with hippocampus and amygdala volumes. Amygdala and hippocampus volumes were not associated with ApoE4 genotype in AD or MCI. Our data indicate that multicentre acquisition of MRI data using manual volumetry is reliable and feasible for cross-sectional diagnostic studies, and they replicate essential findings from smaller scale monocentre studies.

Subjective memory complaints in community dwelling healthy older people: the influence of brain and psychopathology†

Subjective memory complaints (SMC) are common. We aimed to characterize the relationship between psychiatric illness and white matter disease to SMC in a sample of healthy older people.

Multidimensional biomarker-based diagnosis of early Alzheimer's disease

Drosophila motorneurons, and found that it became highly phosphorylated and did not bind effectively to microtubules. Furthermore, humantau expression reduced the microtubule binding of endogenous tau and resulted in a dramatic phosphorylation-dependent reduction in the number of axonal microtubules. We further found that human and Drosophila tau can be co-immunoprecipitated from the fly brain, and that the phosphorylation state of the Drosophila-tau itself was not dramatically altered. Conclusions: We find that in vivo expression of hyperphosphorylated human-tau is able to disrupt the microtubule-binding function of the normal endogenous Drosophila-tau and hence cause the destabilization of microtubules. The mechanism by which this occurs probably does not involve modulation of the phosphorylation state of the Drosophila-tau, but may be via a physical interaction between the two forms of tau. Interestingly, we demonstrate an interaction between normal and abnormal forms of tau in the absence of any tau filaments. This implies that the sequesteration of normal tau by hyper-phosphorylated tau is not dependant upon the latter accumulating into aggregates and physically trapping the normal tau, but rather due to a phosphorylation-dependant toxic-effect of the soluble abnormal tau. We hope that this work may shed light on the mechanism by which abnormal species of tau poison the function of molecules of normal tau within AD neurons, and ultimately inform therapeutic approaches.

Subjective memory complaints are associated with affective disorders but not white matter hyperintensities in a sample of community dwelling healthy older people

Internal capsular genu infarcts infrequently cause cognitive impairment and behavioral changes, and little is known about the underlying mechanism. Using diffusion-tensor imaging (DTI) and the fractional anisotropy (FA) index in the region of interest (ROI) and ipsilesional frontal cortex, we evaluated two patients with internal capsular genu infarction who presented with frontal dysfunction and cognitive impairment. The reported findings help to elucidate the mechanism underlying cognitive deterioration in internal capsular genu infarction. J Korean Neurol Assoc 28(2):104-107, 2010

Lower body mass index associated with higher CSF levels of tau pathology in Alzheimer's Disease

carer. Consent to fasting blood sampling was obtained in 413 subjects. Serum glucose was determined using an enzymatic/colorimetric method. Results: Participants were on average 87.1 6 4.3 years old, 72.0% women, and had a mean 5.4 6 2.6 years of education. During follow-up about one third of the participants developed dementia. A history of diabetes was present in 12.3% of dementia incident cases and in 12.4% of the non-demented elderly (p1⁄4 0.96). Mean glucose concentrations at baseline did not significantly differ between subjects with incident dementia (93.8 6 26.0 mg/dL) and nondemented elderly (98.2 6 37.2 mg/dL), (p 1⁄4 0.17). Conclusions: The present prospective population-based study failed to demonstrate a significant association between diabetes or glucose concentration and dementia in the very old.

Alterations in activation between mild cognitive impaired subjects during a working memory task and resting coherent network

PET and FDG-PET in diagnosing AD. Methods: The diagnosis for MCI and probable AD followed the MCI clinical criteria presented by Petersen et al. (Petersen et al. 1999) and National Institute of Neurological and Communication Disorders, Alzheimer’s Disease and Related Disorders Association (McKhann et al. 1984), respectively. [11C]-BF-227 was synthesized from the precursor by N-methylation in dimethyl sulfoxide using [11C]-methyl triflate. The [11C]-BF-227 PET study was performed using a PET SET-2400 W scanner (Shimadzu Inc., Japan).Cerebral glucose metabolism was measured using 18F-FDG and a PET scanner SET-2400 W. Subjects were scanned in a quiet and dimly-lit room with their eyes closed after at least four hours of food restriction. Results: Patients with MCI subjects showed significantly increased accumulation of [11C]-BF-227 compared to AN in frontal, temporal, parietal, and occipital cortices as well as anterior and posterior cingulate gyrus. On the other hand SUV-R of BF-227 was lower in MCI compared to AD in lateral temporal, parietal, and occipital cortices, posterior cingulate gyrus, and striatum. SUV-R of BF-227 was negatively correlated with that of FDG when we analyzed the data from all the subjects (AN, MCI, and AD) together. The specificity and sensitivity for diagnosis of AD with BF-227 were significantly better than those with FDG-PET. Conclusions: We conclude that BF-227 PET is a useful technology in diagnosing MCI or an early stage of AD with very little invasion. These results indicate that MCI has intermediate retention of 11C-BF-227 between AN and AD indicating that Ab deposition already started in the stage of MCI before dementia symptoms become obvious.

Significantly altered BACE1 levels have been found in the blood of Alzheimer's disease and MCI subjects

Background: The progressive formation of amyloid plaques consisting of the 4-KD amyloid b-peptide (Ab) has long been considered the pathological hallmark of Alzheimer’s disease (AD). Beta-secretase (BACE1) is one of the two key enzymes in processing the amyloid precursor protein (APP) to produce Ab. We and others recently discovered that BACE1 activity was significantly increased in sporadic AD brains (Yang et al., 2003) and that the concentrations of both CSF BACE1 enzymatic activity and protein were significantly increased in subjects with amnestic mild cognitive impairment (MCI) (Zhong et al., 2007). Methods: We have hypothesized that by using BACE1 as a biomarker candidate in plasma, it may aid in early detection and prediction of AD in the at risk predementia MCI stage. Post-mortem studies have shown that the APOE-e4 genotype is associated with an increase in Ab production, and the e4 isoform may regulate the generation of Ab. Moreover, memory declined in APOE-e4 carriers even before the symptomatic presentation of MCI and before the age of 60. Results: Interestingly, we have found that the highest significantly elevated BACE1 concentrations were in the CSF of MCI APOEe4 carriers (Ewers et al., 2008). Lumbar punctures, however, are considered an invasive procedure it may be difficult to obtain the sample size necessary for biomarker validation studies, or for a broad clinical screening with a diagnostic indicator. Therefore, potential biomarkers from a more accessible source, such as blood plasma from certain types of cells, are critical for advancement. To our knowledge, this is the first time blood has been examined for BACE1 functional proteins and enzyme activity, as well as the enzymatic product, sAPPb and total Ab1-x. As expected, we found significant changes among BACE1 functional proteins in the blood from subjects with MCI and AD compared to age-matched cognitively normal controls. Conclusions: These finding are highly relevant for the improved hypothesis driven generation of biomarkers for AD, regarding early detection and prediction, as well as for assessment of mechanisms for amyloid lowering compounds currently in phase I-III clinical trials. Potential molecular mechanisms of BACE 1 in the blood will be discussed in this paper.