Stefan Klöppel

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

Are you Stefan Klöppel?

Claim your profile

Publications (103)690.17 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Clinical Alzheimer's disease affects both cerebral hemispheres to a similar degree in clinically typical cases. However, in atypical variants like logopenic progressive aphasia, neurodegeneration often presents asymmetrically. Yet, no in vivo imaging study has investigated whether lateralized neurodegeneration corresponds to lateralized amyloid-β burden. Therefore, using combined (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography, we explored whether asymmetric amyloid-β deposition in Alzheimer's disease is associated with asymmetric hypometabolism and clinical symptoms. From our database of patients who underwent positron emission tomography with both (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose (n = 132), we included all amyloid-positive patients with prodromal or mild-to-moderate Alzheimer's disease (n = 69). The relationship between (11)C-Pittsburgh compound B binding potential and (18)F-fluorodeoxyglucose uptake was assessed in atlas-based regions of interest covering the entire cerebral cortex. Lateralizations of amyloid-β and hypometabolism were tested for associations with each other and with type and severity of cognitive symptoms. Positive correlations between asymmetries of Pittsburgh compound B binding potential and hypometabolism were detected in 6 of 25 regions (angular gyrus, middle frontal gyrus, middle occipital gyrus, superior parietal gyrus, inferior and middle temporal gyrus), i.e. hypometabolism was more pronounced on the side of greater amyloid-β deposition (range: r = 0.41 to 0.53, all P < 0.001). Stronger leftward asymmetry of amyloid-β deposition was associated with more severe language impairment (P < 0.05), and stronger rightward asymmetry with more severe visuospatial impairment (at trend level, P = 0.073). Similarly, patients with predominance of language deficits showed more left-lateralized amyloid-β burden and hypometabolism than patients with predominant visuospatial impairment and vice versa in several cortical regions. Associations between amyloid-β deposition and hypometabolism or cognitive impairment were predominantly observed in brain regions with high amyloid-β load. The relationship between asymmetries of amyloid-β deposition and hypometabolism in cortical regions with high amyloid-β load is in line with the detrimental effect of amyloid-β burden on neuronal function. Asymmetries were also concordant with lateralized cognitive symptoms, indicating their clinical relevance. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 08/2015; DOI:10.1093/brain/awv229 · 10.23 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 0.98. Multi-class separation of 138 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 and 0.78 for FTD) on data 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.
    Journal of Alzheimer's disease: JAD 08/2015; 47(4). DOI:10.3233/JAD-150334 · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Executive deficits are frequent sequelae of neurological and psychiatric disorders, but their adequate neuropsychological assessment is still a matter of contention, given that executive tasks draw on a multitude of cognitive processes that are often not sufficiently specified. In line with this, results on psychometric properties of the Tower of London, a task measuring planning ability as a prototypical executive function, are equivocal and furthermore lacking completely for adult clinical populations. We used a structurally balanced item set implemented in the Tower of London (Freiburg version, TOL-F) that accounts for major determinants of problem difficulty beyond the commonly used minimum number of moves to solution. Split-half reliability, internal consistency, and criterion-related concurrent validity of TOL-F accuracy were assessed in patients with stroke (N=60), Parkinson syndrome (N=51), and mild cognitive impairment (N=29), and healthy adults (N=155). Across samples, mean split-half and lower-bound indices of reliability of accuracy scores were adequate (r≥.7) or higher. Compared to a subset of healthy controls matched for age, sex, and education levels, deficits in planning accuracy emerged for all three clinical samples. Based on consistently adequate reliability and a good criterion-related validity of accuracy scores, the TOL-F demonstrates its utility for testing planning ability in clinical samples and healthy adults. Using item sets systematically accounting for several determinants of task difficulty can thus significantly enhance the contended reliability of executive tasks and provide an opportunity to resolve the underspecification of cognitive processes contributing to executive functioning in health and disease. Copyright © 2015. Published by Elsevier Ltd.
    Neuropsychologia 07/2015; 75(August):646–655. DOI:10.1016/j.neuropsychologia.2015.07.017 · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to investigate pathological mechanisms underlying brain tissue alterations in mild cognitive impairment (MCI) using multi-contrast 3 T magnetic resonance imaging (MRI).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We present in this paper a method to perform a length parameterization of cortical sulcus meshes. Such parameterization allows morphological features to be localized in a normalized way along the length of the sulcus and can be used to perform population studies and group comparisons. Our method uses the second eigenfunction of the Laplace-Beltrami operator, and the resulting parameterization is quasi-isometric. The process is validated on the central sulci of a set of subjects and its efficiency is demonstrated by quantifying morphological differences between left and right-handed subjects.
    IEEE International Symposium on Biomedical Imaging, Brooklyn, USA; 04/2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Processing of multiple or bilateral conditions presented simultaneously in both hemifields reflects the natural mode of perception in our multi-target environment, but is not yet completely understood. While region-of-interest based studies in healthy subjects reported single cortical areas as the right inferior parietal lobe (IPL) or temporoparietal junction (TPJ) to process bilateral conditions, studies in extinction patients with reduced ability in this regard suggested the right superior temporal cortex to hold a key role. The present fMRI study on healthy subjects aimed at resolving these discrepancies by contrasting bilateral versus unilateral visual conditions in a paradigm similar to the bed-side test for patients with visual extinction on a whole brain level. Additionally, reduced attentional capacity in spatial processing was investigated in normal aging. Processing of bilateral conditions compared to unilateral ones showed to require stronger activation of not one single cortical region but the entire right-lateralized ventral attention network, bilateral parietal and visual association areas. These results might suggest a conceptual difference between unilateral and bilateral spatial processing with the latter depending on additional anatomical and functional brain resources. Reduced attentional capacity in elderly subjects was associated with compensatory recruitment of contralateral functional homologues [left IPL, TPJ, frontal eye field (FEF)]. These data reveal the functional anatomy of our ability to visually process and respond to the entity of the environment and improve our understanding of neglect and extinction. Moreover, the data demonstrate that a restriction of the attentional capacity is based on processing limitations in the network of high-level cortical areas and not due to restriction in the primary sensory ones. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cortex 03/2015; 66. DOI:10.1016/j.cortex.2015.02.018 · 6.04 Impact Factor
  • Jessica Peter · Stefan Klöppel
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer’s disease (AD), the predominant cause of dementia, is characterized by progressive loss of memory and other cognitive functions with advancing age, and both genetic and non-genetic factors modifying disease risk. This chapter provides a summary of the underlying neuropathology, epidemiology, and clinical characteristics of AD. Additionally, recently developed methods of automated diagnosing, novel therapeutic strategies, and possible preventing variables are briefly described.
    Brain Mapping: An Encyclopedic Reference, First Edition edited by Arthur W. Toga, 02/2015: chapter 73; Elsevier., ISBN: 9780123970251
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Deterministic dynamic causal modeling (DCM) for fMRI data is a sophisticated approach to analyse effective connectivity in terms of directed interactions between brain regions of interest. To date it is difficult to know if acquired fMRI data will yield precise estimation of DCM parameters. Focusing on parameter identifiability, an important prerequisite for research questions on directed connectivity, we present an approach inferring if parameters of an envisaged DCM are identifiable based on information from fMRI data. With the freely available "attention to motion" dataset, we investigate identifiability of two DCMs and show how different imaging specifications impact on identifiability. We used the profile likelihood, which has successfully been applied in systems biology, to assess the identifiability of parameters in a DCM with specified scanning parameters. Parameters are identifiable when minima of the profile likelihood as well as finite confidence intervals for the parameters exist. Intermediate epoch duration, shorter TR and longer session duration generally increased the information content in the data and thus improved identifiability. Irrespective of biological factors such as size and location of a region, attention should be paid to densely interconnected regions in a DCM, as those seem to be prone to non-identifiability. Our approach, available in the DCMident toolbox, enables to judge if the parameters of an envisaged DCM are sufficiently determined by underlying data without priors as opposed to primarily reflecting the Bayesian priors in a SPM-DCM. Assessments with the DCMident toolbox prior to a study will lead to improved identifiability of the parameters and thus might prevent suboptimal data acquisition. Thus, the toolbox can be used as a preprocessing step to provide immediate statements on parameter identifiability.
    Frontiers in Neuroscience 02/2015; 9:43. DOI:10.3389/fnins.2015.00043 · 3.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Voxel-based morphometry from conventional T1-weighted images has proved effective to quantify Alzheimer's disease (AD) related brain atrophy and to enable fairly accurate automated classification of AD patients, mild cognitive impaired patients (MCI) and elderly controls. Little is known, however, about the classification power of volume-based morphometry, where features of interest consist of a few brain structure volumes (e.g. hippocampi, lobes, ventricles) as opposed to hundreds of thousands of voxel-wise gray matter concentrations. In this work, we experimentally evaluate two distinct volume-based morphometry algorithms (FreeSurfer and an in-house algorithm called MorphoBox) for automatic disease classification on a standardized data set from the Alzheimer's Disease Neuroimaging Initiative. Results indicate that both algorithms achieve classification accuracy comparable to the conventional whole-brain voxel-based morphometry pipeline using SPM for AD vs elderly controls and MCI vs controls, and higher accuracy for classification of AD vs MCI and early vs late AD converters, thereby demonstrating the potential of volume-based morphometry to assist diagnosis of mild cognitive impairment and Alzheimer's disease.
    Clinical neuroimaging 11/2014; 7. DOI:10.1016/j.nicl.2014.11.001 · 2.53 Impact Factor
  • Source
    Elisa Scheller · Lora Minkova · Mathias Leitner · Stefan Klöppel
    [Show abstract] [Hide abstract]
    ABSTRACT: Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of "attempted" and "successful" compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington's disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset.
    Frontiers in Psychiatry 09/2014; 5:132. DOI:10.3389/fpsyt.2014.00132
  • [Show abstract] [Hide abstract]
    ABSTRACT: Visual neglect results from dysfunction within the spatial attention network. The structural connectivity in undamaged brain tissue in neglect has barely been investigated until now. In the present study, we explored the microstructural white matter characteristics of the contralesional hemisphere in relation to neglect severity and recovery in acute stroke patients. We compared age-matched healthy subjects and three groups of acute stroke patients (9 ± 0.5 days after stroke): (i) patients with nonrecovered neglect (n = 12); (ii) patients with rapid recovery from initial neglect (within the first week post-stroke, n = 7), (iii) stroke patients without neglect (n = 17). We analyzed the differences between groups in grey and white matter density and fractional anisotropy (FA) and used fiber tracking to identify the affected fibers. Patients with nonrecovered neglect differed from those with rapid recovery by FA-reduction in the left inferior parietal lobe. Fibers passing through this region connect the left-hemispheric analogues of the ventral attention system. Compared with healthy subjects, neglect patients with persisting neglect had FA-reduction in the left superior parietal lobe, optic radiation, and left corpus callosum/cingulum. Fibers passing through these regions connect centers of the left dorsal attention system. FA-reduction in the identified regions correlated with neglect severity. The study shows for the first time white matter changes within the spatial attention system remote from the lesion and correlating with the extent and persistence of neglect. The data support the concept of neglect as disintegration within the whole attention system and illustrate the dynamics of structural-functional correlates in acute stroke. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 09/2014; 35(9). DOI:10.1002/hbm.22503 · 6.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Corrupted gradient directions (GD) in diffusion weighted images may seriously affect reliability of diffusion tensor imaging (DTI)-based comparisons at the group level. In the present study we employed a quality control (QC) algorithm to eliminate corrupted gradient directions from DTI data. We then assessed effects of this procedure on comparisons between Huntington disease (HD) subjects and controls at the group level. Methods Sixty-one HD patients in early stages and forty matched healthy controls were studied in a longitudinal design (baseline and two follow-ups at three time points over 15 months), in a multicenter setting with similar acquisition protocols on four different MR scanners at four European study sites. A QC algorithm was used to identify corrupted GD in DTI data sets. Differences in fractional anisotropy (FA) maps at the group level with and without elimination of corrupted GD were analyzed. Results The elimination of corrupted GD had an impact on individual FA maps as well as on cross-sectional group comparisons between HD subjects and controls. Following application of the QC algorithm, less small clusters of FA changes were observed, compared to the analysis without QC. However, the main pattern of regional reductions and increases in FA values with and without QC-based elimination of corrupted GD was unchanged. Conclusion An impact on the result patterns of the comparison of FA maps between HD subjects and controls was observed depending on whether QC-based elimination of corrupted GD was performed. QC-based elimination of corrupted GD in DTI scans reduces the risk of type I and type II errors in cross-sectional group comparison of FA maps contributing to an increase in reliability and stability of group comparisons.
    BioMedical Engineering OnLine 09/2014; 13(1):128. DOI:10.1186/1475-925X-13-128 · 1.75 Impact Factor
  • Source
    Alzheimer's Association International Conference, Copenhagen; 07/2014
  • Source
    Alzheimer's and Dementia 07/2014; 10(4):P541-P542. DOI:10.1016/j.jalz.2014.05.868 · 17.47 Impact Factor
  • Source
    Alzheimer's and Dementia 07/2014; 10(4):P846. DOI:10.1016/j.jalz.2014.05.1672 · 17.47 Impact Factor
  • Source
    Alzheimer's and Dementia 07/2014; 10(4):P824. DOI:10.1016/j.jalz.2014.05.1624 · 17.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although episodic memory impairment is usually the earliest sign of Alzheimer's disease (AD), there are up to 15% of patients presenting with early impairment in non-memory cognitive functions (i.e., atypical AD). Stratifying patients with AD may aid clinical trials. Previous studies divided patients by cognitive profile, focusing on cross-sectional analyses without testing stability of clusters over time. We used principal component analysis followed by cluster analyses in 127 patients with AD based on 24 cognitive scores at 0, 6, 12, and 24 months follow-up. We investigated the definition of clusters and their stability over time as well as interactions of cluster assignment and disease severity. At each time point, six distinct factors and four distinct clusters were extracted that did not differ substantially between time points. Clusters were defined by cognitive profile rather than disease severity. 85% of patients fell into the same cluster twice, 42% three times, and 17% four times. Subjects with focal semantic impairment progressed significantly faster than the other cluster. Longitudinally, focal deficits increased relatively rather than tending toward average disease severity. The observed similar cluster definitions at each time point indicate the validity of the approach. Cluster-specific longitudinal increases of focal impairments and significant between-cluster differences in disease progression make this approach useful for stratified inclusions into clinical trials.
    Journal of Alzheimer's disease: JAD 06/2014; 42(2). DOI:10.3233/JAD-140261 · 4.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Long-term potentiation (LTP) is a key element of synaptic plasticity. At the macroscopic level, similar effects can be induced in the human brain using repetitive stimulation with identical stimuli. High-frequency stimulation (HFS) can increase neuronal responses whereas low-frequency stimulation may produce the opposite effect. Optimal stimulation frequencies and characteristics for inducing stimulus-specific response modification differ substantially from those applied to brain tissue slices but have been explored in recent studies. In contrast, the individual manifestation of this effect in terms of its spatial location and extent are unclear. Using functional MRI (fMRI) in 18 subjects (mean age 25.3 years), we attempted to induce LTP-like effects by HFS with checkerboard flashes at 9 Hz for 120 seconds. As expected, flashes induced strong activation in primary and secondary visual cortices. Contrary to our expectations, we found clusters of decreased activations induced by pattern flashes after HFS at the border between primary and secondary visual cortices.. On the level of the individual subject, some showed significantly increased activations in the post-HFS session while the majority showed significant decreases. The locations of areas showing altered activations before and after HFS were only partly overlapping. No association between location, extent and direction of the HFS-effect was observed. The findings are unexpected in the light of existing HFS-studies, but mirror the high inter-subject variability, concerning even the directionality of the induced effects shown for other indices of LTP-like plasticity in the human brain. As this variability is not observed in LTP at the cellular level, a better understanding of LTP-like mechanisms on the macroscopic level is essential for establishing tools to quantify individual synaptic plasticity in-vivo.
    Frontiers in Human Neuroscience 06/2014; 8(695). DOI:10.3389/fnhum.2014.00695 · 2.90 Impact Factor
  • Joint Congress of European Neurology; 05/2014

Publication Stats

3k Citations
690.17 Total Impact Points

Institutions

  • 2011–2015
    • Universitätsklinikum Freiburg
      • Department of Psychiatry and Psychotherapy
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2007–2015
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
    • Universität Hamburg
      • Department of Neurology
      Hamburg, Hamburg, Germany
    • University College London
      • Wellcome Department of Imaging Neuroscience
      London, ENG, United Kingdom
  • 2007–2012
    • University Medical Center Hamburg - Eppendorf
      • Department of Systems Neuroscience
      Hamburg, Hamburg, Germany