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Several studies have demonstrated that fully automated pattern recognition methods applied to structural magnetic resonance imaging (MRI) aid in the diagnosis of dementia, but these conclusions are based on highly preselected samples that significantly differ from that seen in a dementia clinic. At a single dementia clinic, we evaluated the ability of a linear support vector machine trained with completely unrelated data to differentiate between Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia, and healthy aging based on 3D-T1 weighted MRI data sets. Furthermore, we predicted progression to AD in subjects with mild cognitive impairment (MCI) at baseline and automatically quantified white matter hyperintensities from FLAIR-images. Separating additionally recruited healthy elderly from those with dementia was accurate with an area under the curve (AUC) of 0.97 (according to Fig. 4). Multi-class separation of patients with either AD or FTD from other included groups was good on the training set (AUC >  0.9) but substantially less accurate (AUC = 0.76 for AD, AUC = 0.78 for FTD) on 134 cases from the local clinic. Longitudinal data from 28 cases with MCI at baseline and appropriate follow-up data were available. The computer tool discriminated progressive from stable MCI with AUC = 0.73, compared to AUC = 0.80 for the training set. A relatively low accuracy by clinicians (AUC = 0.81) illustrates the difficulties of predicting conversion in this heterogeneous cohort. This first application of a MRI-based pattern recognition method to a routine sample demonstrates feasibility, but also illustrates that automated multi-class differential diagnoses have to be the focus of future methodological developments and application studies.

A novel method of automated MRI volumetry was used to study regional atrophy and disease progression in repeated MRI measurements of patients with frontotemporal lobar degeneration (FTLD). Fifty-nine structural MRI data sets of 17 clinically diagnosed FTLD patients were acquired over up to 30 months in intervals of 6 months and compared with data of 30 age-matched healthy controls. Patients were further subgrouped into behavioral variant FTLD (bvFTLD), progressive nonfluent aphasia (PNFA), and semantic dementia (SemD). Gray matter (GM) volumes of frontal lobes (FL) and temporal lobes (TL) were determined by voxel-based volumetry based on SPM5 algorithms and a probabilistic brain atlas. MRI volumetry revealed frontal and temporal GM atrophy across FTLD patients, with further progression over time. Significant side asymmetry of TL volumes was found in SemD. The ratio of TL to FL volumes was significantly reduced in SemD and increased in bvFTLD. Using this ratio, 6/7 SemD patients and 5/6 bvFTLD patients could be correctly differentiated. TL/FL ratios in bvFTLD and SemD further diverged significantly over a time span of only 6 months. Rates of temporal GM loss per 6 months were 3-4% in SemD, and 2.5% for frontal GM loss in bvFTLD, and thereby clearly exceeded published cerebral volume loss in healthy elderly subjects. The study presents a fully automated, observer-independent volumetric assessment of regional atrophy which allows differentiation of FTLD subgroups. Its sensitivity for atrophy progression--even in such short intervals like 6 months--might benefit future clinical trials as treatment outcome measure., (Copyright © 2011 Wiley-Liss, Inc.)

Structural MRI markers may serve as surrogate endpoints in clinical trials on disease modification in Alzheimer's disease (AD). Here, we used a longitudinal MRI data set of total brain and cortical grey matter volumes from 66 patients with AD recruited across seven centres of the German Dementia Competence Network. We compared effect size estimates for the detection of a 25% reduction of atrophy progression between a priori segmentation of brain tissue, implementing an anatomical model of brain tissue distribution, and a posteriori segmentation that was not informed by an anatomical model. Additionally, we compared effect size estimates between fixed effects analysis and a mixed effects model, implementing a random effects term to account for variable spacing of observation times. A priori segmentation reduced the required sample size by 50%. Introducing a random effects term for time led to an additional 50% reduction of required samples sizes compared to fixed effects analysis. In summary, using a priori segmentation with mixed effects analysis reduced the sample size to detect clinically relevant treatment effects more than fourfold. The implementation of mixed effects models will enhance the power to detect treatment effects also with other classes of biological endpoints including molecular biomarkers of disease.

Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer's disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage. [ABSTRACT FROM AUTHOR]

Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer's disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD. Methods: WM hyperintensity volume on fluid-attenuated inversion recovery images of 201 patients with AD (128 carriers and 73 non-carriers of the APOE Ɛ4 risk allele) was determined globally as well as regionally with voxelbased lesion mapping. Clinical, neuropsychological and MRI data were collected from prospective multicenter trials conducted by the German Dementia Competence Network. Results: WM hyperintensity volume was significantly greater in non-carriers of the APOE Ɛ4 allele. Lesion distribution was similar among Ɛ4 carriers and non-carriers. Only Ɛ4 non-carriers showed a correlation between lesion volume and cognitive performance. Conclusion: The current findings indicate an increased prevalence of WM hyperintensities in non-carriers compared with carriers of the APOE Ɛ4 allele among patients with AD. This is consistent with a possibly more pronounced contribution of heterogeneous vascular risk factors to WM damage and cognitive impairment in patients with AD without APOE Ɛ4-mediated risk. [ABSTRACT FROM AUTHOR]

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD. [ABSTRACT FROM AUTHOR]

Background: The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer's disease (AD) and has recently been found to modulate disease expression in patients with AD. Objective: To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years. Methods: Subjects converting to AD (n = 63) were compared to a control group with stable mild cognitive impairment (n = 131). Clinical, neuropsychological, and MRI data were obtained by the German Dementia Competence Network. Subgroups of converting and stable APOE E4 carriers and non-carriers were investigated longitudinally with MRI to examine structural correlates of conversion. Voxel-based morphometry was applied to investigate gray matter distribution. Results: At baseline, executive performance correlated with global and bilateral prefrontal gray matter volume and predicted conversion only among non-carriers. Converting carriers and non-carriers presented distinct patterns of brain atrophy on longitudinal analysis, in line with a dissociation between more pronounced occipital atrophy in carriers and more frontoparietal volume loss in non-carriers at follow-up. Conclusions: The current findings suggest that in APOE E4 non-carriers with AD, executive dysfunction is closely linked to frontal gray matter atrophy and predictive of progression to dementia. The results are consistent with APOE genotype-dependent profiles of structural damage and cognitive decline in patients with imminent conversion to AD. [ABSTRACT FROM AUTHOR]

Background: Studies on anomia treatment in semantic dementia demonstrate that re-learning is possible, but maintenance and generalisation of improvements are limited. Changes in cortical activation associated with anomia treatment have already been demonstrated in aphasic patients after stroke. Recovery of brain functions under the impact of deficit-specific treatment in semantic dementia has not been explored yet. Nevertheless, recent activation studies using language tasks in patients with neurodegenerative diseases report altered activation patterns, involving diverse brain regions ipsi- or contralateral to the primarily affected left hemisphere. Aims: The purpose of the present study was to investigate if phonological and semantic cueing hierarchies established for naming therapy in aphasia were also effective in a patient with semantic dementia. Moreover, we aimed to examine changes of brain activity associated with anomia treatment. Methods & Procedures: One individual with semantic dementia participated in the present study. Over a period of 4 weeks the participant received an intensive model-oriented treatment with phonological and semantic cueing hierarchies. Two pre-tests and two post-tests (one immediately after training and one 2 months later) were administered. The second pre-test and both follow-ups were registered inside the scanner. Outcomes & Results: Behaviourally, both treatments resulted in specific training effects, which subsequently decreased over time. Concerning functional magnetic resonance imaging data, improved naming following therapy was mirrored by changes in cortical activity, predominantly located in right superior and inferior temporal gyrus. Conclusions: Cueing hierarchies were successful, resulting in specific and immediate treatment effects, corroborating previous treatment studies in semantic dementia. Treatment-induced changes in cortical activity were mainly concentrated in right temporal cortex. Since right-sided modulation of cortical activity was associated with training-induced improvements in task performance, it may reflect right hemispheric compensatory mechanisms in this participant. [ABSTRACT FROM AUTHOR]

The precuneus is part of the default network of the human brain, which exhibits a high level of activity during the resting state and lower activity during task-related behavior. Typically, the posterior midline areas show this characteristic response in functional magnetic resonance imaging (fMRI) studies. In Alzheimer's disease (AD) and mild cognitive impairment (MCI), subjects exhibit a lack of this typical deactivation. The interpretation of these findings, however, is obfuscated by the presence of local pathology and atrophy in AD. In contrast to AD, in patients with early frontotemporal lobar degeneration (FTLD), the precuneus is virtually free of local neuropathology. In this study, we demonstrate reduced fMRI signal in the precuneus in a group of patients with FTLD during a confrontation naming task. We show that this effect in FTLD patients was (1) similar to that observed in AD and MCI and (2) not related to the degree of gray matter atrophy in the precuneus. We hypothesize that reduced deactivation of the default network is not related to local pathology but to a lack of connectivity, which decreases in both FTLD and AD, the major cortical dementias. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractWe present the case of a 71-year-old woman with an 11-year history of slowly progressive decline of motor speech. Normal clinical investigations including routine magnetic resonance imaging (MRI) at 7, 8 and 10 years after the onset of speech dysfunction led to the suggestion of a psychogenic disorder. Extensive clinical, neuropsychological and neuroimaging investigations including 18 F-desoxyglucose-positron emission tomography (PET), quantitative MRI and MR spectroscopy were performed to look for subtle brain pathology. Quantitative assessment of 3D-MRI, F-desoxyglucose-PET and magnetic resonance spectroscopy all demonstrated clear evidence of multifocal frontotemporal brain pathology that had not been picked up on routine MRI investigations on previous admissions. This is the longest benign history of slowly progressive anarthria reported so far. It demonstrates a possible role of quantitative neuroimaging techniques in the diagnosis of complex neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Abstract Mutations in the presenilin-1 gene (PS-1 gene) on chromosome 14 have recently been identified as a cause of familial early-onset Alzheimer's disease (EOAD). To our knowledge, only two German EOAD patients with mutations in the PS-1 gene have been identified thus far. Herein we report the case of a German EOAD patient with a family history of dementia and a missense mutation at codon 139 (M139V) of the PS-1 gene. The patient came to our clinic for the first time when he was 44 years old. During the following 7 years, his Mini-Mental State Examination (MMSE) score dropped from 24 to 0. Myocloni were an early neurological symptom that was already present during the first consultation. We could demonstrate that myoclonic activity was of cortical origin using a back-averaging method. Magnetic resonance imaging (MRI) revealed only slight changes in the early stage of the disease. Follow-up MRI studies showed progression of bitemporal ventricular enlargement and progressive frontal and temporal cortical atrophy. Although the majority of EOAD patients belong to the sporadic (non-genetic) type of AD, early-onset dementia, early myocloni and a familial history of AD should direct attention to the possibility of a genetic form of AD. [ABSTRACT FROM AUTHOR]

Abstract: Little and controversial evidence is available from neuroimaging studies in progressive nonfluent aphasia (PNA). The goal of this study was to combine information from different imaging modalities in PNA compared with Alzheimer''s disease (AD). Chemical shift imaging (CSI), voxel-based morphometry (VBM) and fluorodeoxyglucose positron emission tomography (FDG-PET) were used in 5 PNA, 10 AD patients and 10 normal subjects. Group comparisons revealed left anterior lateral temporal abnormalities (BA20/21) in PNA using CSI, VBM and PET in comparison to normal subjects. AD patients showed more limited hypometabolism within the same area. In addition left lateral parietal (BA40) abnormalities were demonstrated in our PNA as well as our AD group using PET and VBM (AD group only). Combining information from all imaging modalities on a single case basis revealed pathology within the left anterior lateral temporal and lateral parietal lobe both in PNA and AD. PNA and AD patients differed significantly, however, with respect to the frequency of medial temporal lobe and posterior cingulate/precuneus involvement. Although our results might not be generalizable to all subgroups of PNA, we conclude that medial temporal and posterior cingulate/precuneus cortex pathology as assessed by CSI and VBM or PET distinguish PNA from AD, whereas lateral temporal and parietal areas are involved in both conditions. [Copyright &y& Elsevier]