Publications by authors named "Hans-Jürgen Huppertz"

63 Publications

Genotype-Phenotype Relations for the Atypical Parkinsonism Genes: MDSGene Systematic Review.

Mov Disord 2021 07 19;36(7):1499-1510. Epub 2021 Mar 19.

Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated ("bagged") decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%-86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57-70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28517DOI Listing
July 2021

How to Arrange Follow-Up Time-Intervals for Longitudinal Brain MRI Studies in Neurodegenerative Diseases.

Front Neurosci 2021 15;15:682812. Epub 2021 Jul 15.

Department of Neurology, University of Ulm, Ulm, Germany.

Background: Longitudinal brain MRI monitoring in neurodegeneration potentially provides substantial insights into the temporal dynamics of the underlying biological process, but is time- and cost-intensive and may be a burden to patients with disabling neurological diseases. Thus, the conceptualization of follow-up time-intervals in longitudinal MRI studies is an essential challenge and substantial for the results. The objective of this work is to discuss the association of time-intervals and the results of longitudinal trends in the frequently used design of one baseline and two follow-up scans.

Methods: Different analytical approaches for calculating the linear trend of longitudinal parameters were studied in simulations including their performance of dealing with outliers; these simulations were based on the longitudinal striatum atrophy in MRI data of Huntington's disease patients, detected by atlas-based volumetry (ABV).

Results: For the design of one baseline and two follow-up visits, the simulations with outliers revealed optimum results for identical time-intervals between baseline and follow-up scans. However, identical time-intervals between the three acquisitions lead to the paradox that, depending on the fit method, the first follow-up scan results do not influence the final results of a linear trend analysis.

Conclusions: This theoretical study analyses how the design of longitudinal imaging studies with one baseline and two follow-up visits influences the results. Suggestions for the analysis of longitudinal trends are provided.
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http://dx.doi.org/10.3389/fnins.2021.682812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319674PMC
July 2021

Changes in Cerebral Gray and White Matter in Patients with Pantothenate Kinase-Associated Neurodegeneration: A Long-Term Magnetic Resonance Imaging Follow-Up Study.

J Mov Disord 2021 May 26;14(2):148-152. Epub 2021 May 26.

Department of Radiology, CEDIMAT, Santo Domingo, Dominican Republic.

Objective: To determine the volume changes in gray and white matter during a long-term follow-up in patients suffering from pantothenate kinase-associated neurodegeneration (PKAN).

Methods: Magnetic resonance imaging was repeated in 13 patients and 14 age-matched controls after a mean interval of more than 7 years. T1-weighted sequences were evaluated by fully automated atlas-based volumetry, compared between groups and correlated with disease progression.

Results: The patients did not show generalized cerebral atrophy but did show a significantly faster volume reduction in the globus pallidus during follow-up (between -0.96% and -1.02% per year, p < 0.05 adjusted for false discovery rate) than controls, which was significantly related to the progression in their dystonia scores (p = 0.032).

Conclusion: The volume loss in the globus pallidus over time-together with the accumulation of iron known as the "tiger's eye"-supports the pathophysiologic concept of this nucleus as a center of inhibition and its severe malfunction in PKAN.
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http://dx.doi.org/10.14802/jmd.20102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175809PMC
May 2021

Quantifying progression in primary progressive aphasia with structural neuroimaging.

Alzheimers Dement 2021 Mar 30. Epub 2021 Mar 30.

Department of Neurology, University Hospital Ulm, Ulm, Germany.

Introduction: The term primary progressive aphasia (PPA) sums up the non-fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression.

Methods: Structural brain imaging and an extensive assessment were applied at baseline and up to 4-year(s) follow-up in 269 participants. With automated atlas-based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials.

Results: At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (-17%) and of the left temporal lobe for svPPA (-34%) and lvPPA (-24%). Severest progression within 1-year follow-up occurred in the basal ganglia in nfvPPA (-7%), in the hippocampus/amygdala in svPPA (-9%), and in (medial) temporal regions in lvPPA (-6%).

Conclusion: PPA presents as a left-dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant-specific.
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http://dx.doi.org/10.1002/alz.12323DOI Listing
March 2021

External validation of automated focal cortical dysplasia detection using morphometric analysis.

Epilepsia 2021 04 27;62(4):1005-1021. Epub 2021 Feb 27.

Department of Epileptology, University Hospital Bonn, Bonn, Germany.

Objective: Focal cortical dysplasias (FCDs) are a common cause of drug-resistant focal epilepsy but frequently remain undetected by conventional magnetic resonance imaging (MRI) assessment. The visual detection can be facilitated by morphometric analysis of T1-weighted images, for example, using the Morphometric Analysis Program (v2018; MAP18), which was introduced in 2005, independently validated for its clinical benefits, and successfully integrated in standard presurgical workflows of numerous epilepsy centers worldwide. Here we aimed to develop an artificial neural network (ANN) classifier for robust automated detection of FCDs based on these morphometric maps and probe its generalization performance in a large, independent data set.

Methods: In this retrospective study, we created a feed-forward ANN for FCD detection based on the morphometric output maps of MAP18. The ANN was trained and cross-validated on 113 patients (62 female, mean age ± SD =29.5 ± 13.6 years) with manually segmented FCDs and 362 healthy controls (161 female, mean age ± SD =30.2 ± 9.6 years) acquired on 13 different scanners. In addition, we validated the performance of the trained ANN on an independent, unseen data set of 60 FCD patients (28 female, mean age ± SD =30 ± 15.26 years) and 70 healthy controls (42 females, mean age ± SD = 40.0 ± 12.54 years).

Results: In the cross-validation, the ANN achieved a sensitivity of 87.4% at a specificity of 85.4% on the training data set. On the independent validation data set, our method still reached a sensitivity of 81.0% at a comparably high specificity of 84.3%.

Significance: Our method shows a robust automated detection of FCDs and performance generalizability, largely independent of scanning site or MR-sequence parameters. Taken together with the minimal input requirements of a standard T1 image, our approach constitutes a clinically viable and useful tool in the presurgical diagnostic routine for drug-resistant focal epilepsy.
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http://dx.doi.org/10.1111/epi.16853DOI Listing
April 2021

Focal Cortical Dysplasia: Relevant for Seizures in Phelan-McDermid Syndrome?

Pediatr Neurol 2021 02 14;115:7-9. Epub 2020 Nov 14.

Department of Neurology, University of Ulm, Ulm, Germany.

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http://dx.doi.org/10.1016/j.pediatrneurol.2020.11.005DOI Listing
February 2021

Social cognition in an adult epilepsy patient with developmental amnesia.

Neurocase 2020 08 12;26(4):231-240. Epub 2020 Jul 12.

Swiss Epilepsy Center , Zurich, Switzerland.

Reports on social cognition in patients with developmental amnesia resulting from bilateral hippocampal lesions are rare, although the link between social cognition and temporal lobe structures is well established. We present the case of a 23-year-old male epilepsy patient, BM, with developmental amnesia due to perinatal cerebral hypoxia. The patient was examined with neuroimaging and neuropsychological methods and compared to IQ-matched patients with epilepsy to control for effects of epilepsy. In addition, we used a test battery that evaluates emotion recognition and theory of mind to study his social cognition abilities. Structural high-resolution magnetic resonance imaging showed bilateral hippocampal atrophy. The comparison to controls showed that, in addition to the well-documented memory disorders in developmental amnesia, BM showed remarkable deficits in 9 out of 17 social cognitive tasks assessing emotion recognition and theory of mind. In contrast, BM's performance on tasks of executive functions was largely preserved. The relevance of deficits in social cognition for patients with developmental amnesia is discussed.
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http://dx.doi.org/10.1080/13554794.2020.1791904DOI Listing
August 2020

Focal alterations of the callosal area III in primary lateral sclerosis: An MRI planimetry and texture analysis.

Neuroimage Clin 2020 21;26:102223. Epub 2020 Feb 21.

Department of Neurology, University of Ulm, Germany. Electronic address:

Background: The regional distribution of cerebral morphological alterations in primary lateral sclerosis (PLS) is considered to include the area III of the corpus callosum (CC).

Objective: The study was designed to investigate regional white matter (WM) alterations in the callosal area III by T1 weighted magnetic resonance imaging (T1w-MRI) data in PLS patients compared with healthy controls, in order to identify atrophy and texture changes in vivo.

Methods: T1w-MRI-based white matter mapping was used to perform an operator-independent CC-segmentation for the different areas of the CC in 67 PLS patients vs 82 matched healthy controls and vs 85 ALS patients. The segmentation was followed by texture analysis of the separated CC areas for the PLS patients vs controls and vs ALS patients.

Results: PLS was associated with significant atrophy in the area III of the CC (but not in the other callosal segments), while the alterations in the ALS patients were much more variable and were not significant at the group level. Furthermore, significant regional alterations of the texture parameters entropy and homogeneity in this area were shown in PLS patients and in ALS patients.

Conclusions: This T1w-MRI study demonstrated focused regional CC atrophy and texture alterations limited to the callosal area III (which comprises fibers projecting into the primary motor cortices) in PLS, in comparison to a higher variability in CC size in ALS.
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http://dx.doi.org/10.1016/j.nicl.2020.102223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049663PMC
February 2021

Mutation of the Gene as the Cause of a Severe Hyperkinetic Movement Disorder.

Mov Disord Clin Pract 2020 Jan 7;7(1):88-90. Epub 2019 Nov 7.

Department of Neurology University of Ulm Ulm Germany.

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http://dx.doi.org/10.1002/mdc3.12855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962679PMC
January 2020

Longitudinal brain atrophy distribution in advanced Parkinson's disease: What makes the difference in "cognitive status" converters?

Hum Brain Mapp 2020 04 2;41(6):1416-1434. Epub 2019 Dec 2.

Department of Neurology, University of Ulm, Ulm, Germany.

We investigated the brain atrophy distribution pattern and rate of regional atrophy change in Parkinson's disease (PD) in association with the cognitive status to identify the morphological characteristics of conversion to mild cognitive impairment (MCI) and dementia (PDD). T1-weighted longitudinal 3T MRI data (up to four follow-up assessments) from neuropsychologically well-characterized advanced PD patients (n = 172, 8.9 years disease duration) and healthy elderly controls (n = 85) enrolled in the LANDSCAPE study were longitudinally analyzed using a linear mixed effect model and atlas-based volumetry and cortical thickness measures. At baseline, PD patients presented with cerebral atrophy and cortical thinning including striatum, temporoparietal regions, and primary/premotor cortex. The atrophy was already observed in "cognitively normal" PD patients (PD-N) and was considerably more pronounced in cognitively impaired PD patients. Linear mixed effect modeling revealed almost similar rates of atrophy change in PD and controls. The group comparison at baseline between those PD-N whose cognitive performance remained stable (n = 42) and those PD-N patients who converted to MCI/PDD ("converter" cPD-N, n = 26) indicated suggested cortical thinning in the anterior cingulate cortex in cPD-N patients which was correlated with cognitive performance. Our results suggest that cortical brain atrophy has been already expanded in advanced PD patients without overt cognitive deficits while atrophy progression in late disease did not differ from "normal" aging regardless of the cognitive status. It appears that cortical atrophy begins early and progresses already in the initial disease stages emphasizing the need for therapeutic interventions already at disease onset.
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http://dx.doi.org/10.1002/hbm.24884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267933PMC
April 2020

Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial.

Lancet Neurol 2019 08 2;18(8):724-735. Epub 2019 Jul 2.

German Center for Neurodegenerative Diseases, Munich, Germany; Department of Neurology, Technical University Munich, Munich, Germany; Department of Neurology, Hanover Medical School, Hanover, Germany. Electronic address:

Background: Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy.

Methods: We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1-3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov (NCT02008721) and EudraCT (2012-000928-18), and is completed.

Findings: Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned-47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference -0·94 [SE 1·41; 95% CI -3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity.

Interpretation: 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used.

Funding: ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Lüneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.
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http://dx.doi.org/10.1016/S1474-4422(19)30141-3DOI Listing
August 2019

Combined cerebral atrophy score in Huntington's disease based on atlas-based MRI volumetry: Sample size calculations for clinical trials.

Parkinsonism Relat Disord 2019 06 5;63:179-184. Epub 2019 Feb 5.

Department of Neurology, University of Ulm, Germany.

Introduction: A volumetric MRI analysis of longitudinal regional cerebral atrophy in Huntington's disease (HD) was performed as a read-out of disease progression to calculate sample sizes for future clinical trials.

Methods: This study was based on MRI data of 59 patients with HD and 40 controls recruited within the framework of the PADDINGTON study and investigated at baseline and follow-up after 6 and 15 months. Automatic atlas-based volumetry (ABV) of structural T1-weighted scans was used to calculate longitudinal volume changes of brain structures relevant in HD and to assess standardized effect sizes and sample sizes required for potential future studies.

Results: Atrophy rates were largest in the caudate (-3.4%), putamen (-2.8%), nucleus accumbens (-1.6%), and the parietal lobes (-1.7%); the lateral ventricles showed an expansion by 6.0%. Corresponding effect sizes were -1.35 (caudate), -0.84 (putamen), -0.91 (nucleus accumbens), -1.05 (parietal lobe), and 0.92 (lateral ventricles) leading to N = 36 subjects per study group for detecting a 50% attenuation of atrophy for the best performing structure (caudate). A combined score of volume changes in non-overlapping compartments (striatum, parietal lobes, lateral ventricles) increased the effect size to -1.60 and substantially reduced the required sample sizes by 10 to N = 26 subjects per study group. This combined imaging score correlated significantly both with the CAP score and with the progression of the clinical phenotype.

Conclusion: We propose ABV of the striatum together with parietal lobe and lateral ventricle volumes as a combined imaging read-out for progression studies including clinical trials in HD.
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http://dx.doi.org/10.1016/j.parkreldis.2019.02.004DOI Listing
June 2019

The applause sign in frontotemporal lobar degeneration and related conditions.

J Neurol 2019 Feb 1;266(2):330-338. Epub 2018 Dec 1.

Neurologische Klinik und Poliklinik, Ludwig Maximilians Universität München, Munich, Germany.

The applause sign, i.e., the inability to execute the same amount of claps as performed by the examiner, was originally reported as a sign specific for progressive supranuclear palsy (PSP). Recent research, however, has provided evidence for the occurrence of the applause sign in various conditions. The aim of this study was to determine the prevalence of the applause sign and correlate its presence with neuropsychological and MRI volumetry findings in frontotemporal lobar degeneration and related conditions. The applause sign was elicited with the three clap test (TCT), with a higher score indicating poorer performance. Data were recorded from 272 patients from the cohort of the German consortium for frontotemporal lobar degeneration (FTLDc): 111 with behavioral variant frontotemporal dementia (bvFTD), 98 with primary progressive aphasia (PPA), 30 with progressive supranuclear palsy Richardson's syndrome, 17 with corticobasal syndrome (CBS) and 16 with amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). For comparison, 29 healthy elderly control subjects (HC) were enrolled in the study. All subjects underwent detailed language and neuropsychological assessment. In a subset of 156 subjects, atlas-based volumetry was performed. The applause sign occurred in all patient groups (40% in PSP, 29.5% in CBS, 25% in ALS/FTD, 13.3% in PPA and 9.0% in bvFTD) but not in healthy controls. The prevalence was highest in PSP patients. It was significantly more common in PSP as compared to bvFTD, PPA and HC. The comparison between the other groups failed to show a significant difference regarding the occurrence of the applause sign. The applause sign was highly correlated to a number of neuropsychological findings, especially to measures of executive, visuospatial, and language function as well as measures of disease severity. TCT scores showed an inverse correlation with the volume of the ventral diencephalon and the pallidum. Furthermore the volume of the ventral diencephalon and pallidum were significantly smaller in patients displaying the applause sign. Our study confirms the occurrence of the applause sign in bvFTD, PSP and CBS and adds PPA and ALS/FTD to these conditions. Although still suggestive of PSP, clinically it must be interpreted with caution. From the correlation with various cognitive measures we suggest the applause sign to be indicative of disease severity. Furthermore we suggest that the applause sign represents dysfunction of the pallidum and the subthalamic nucleus, structures which are known to play important roles in response inhibition.
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http://dx.doi.org/10.1007/s00415-018-9134-yDOI Listing
February 2019

Serum neurofilament light chain in behavioral variant frontotemporal dementia.

Neurology 2018 10 12;91(15):e1390-e1401. Epub 2018 Sep 12.

From the Department of Neurology (P.S., S.A.-S., E.S., I.U., C.A.F.v.A., J. Kassubek, B.L., P.O., A.C.L., M.O.) and Institute of Epidemiology and Medical Biometry (B.M.), University of Ulm; Department of Psychiatry and Psychotherapy (J.D.-S., H.F., T.G.), Klinikum Rechts der Isar, Technical University of Munich; Department of Nuclear Medicine (H.B.), Leipzig University Hospital; Department of Neurology (A.D.), Ludwig-Maximilians-University, Munich; Department of Neurology (K.F.), Saarland University, Homburg; Department of Psychiatry and Psychotherapy (K.F.), University of Bonn, Germany; Swiss Epilepsy Center (H.-J.H.), Zurich, Switzerland; Department of Psychiatry and Psychotherapy (H.J.), University Medical Center Hamburg-Eppendorf, Hamburg; AMEOS Klinikum (H.J.), Heiligenhafen; Department of Psychiatry and Psychotherapy (J. Kornhuber, J.M.M.), Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen; Department of Psychiatry and Psychotherapy (M.L.), University of Würzburg; Department of Neurology (J.P.), University of Rostock; DZNE (J.P.), Rostock; Department of Neurodegenerative Diseases and Geriatric Psychiatry (A.S.), University Hospital Bonn; DZNE (A.S.), Bonn; Institute of Human Genetics (A.E.V.), University Medical Center Hamburg-Eppendorf, Hamburg; Department of Psychiatry and Psychotherapy (J.W.), University Medical Center Göttingen; DZNE (J.W.), Göttingen, Germany; iBiMED (J.W.), Medical Sciences Department, University of Aveiro, Portugal; Clinic for Cognitive Neurology (M.L.S.), University Clinic Leipzig; and Max Planck Institute for Human Cognitive and Brain Sciences (M.L.S.), Leipzig, Germany.

Objective: To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD).

Methods: Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry.

Results: At baseline, serum NfL level correlated with CSF NfL (bvFTD = 0.706, < 0.0001; AD/MCI = 0.666, = 0.0003). Highest serum levels were observed in bvFTD ( <0 0.0001 vs Con and MCI, = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD ( = 0.0039 and = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] = 0.4157, = 0.0006; [follow-up] = 0.5629, < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: = -0.5857, < 0.0001; 95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline] = 0.6624, < 0.0001; [follow-up] = 0.5659, = 0.0003) but not with regional brain volumes.

Conclusions: As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials.

Classification Of Evidence: This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia.
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http://dx.doi.org/10.1212/WNL.0000000000006318DOI Listing
October 2018

Ultrasonographic features of focal cortical dysplasia and their relevance for epilepsy surgery.

Neurosurg Focus 2018 09;45(3):E5

1Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich.

OBJECTIVE Surgery has proven to be the best therapeutic option for drug-refractory cases of focal cortical dysplasia (FCD)-associated epilepsy. Seizure outcome primarily depends on the completeness of resection, rendering the intraoperative FCD identification and delineation particularly important. This study aims to assess the diagnostic yield of intraoperative ultrasound (IOUS) in surgery for FCD-associated drug-refractory epilepsy. METHODS The authors prospectively enrolled 15 consecutive patients with drug-refractory epilepsy who underwent an IOUS-assisted microsurgical resection of a radiologically suspected FCD between January 2013 and July 2016. The findings of IOUS were compared with those of presurgical MRI postprocessing and the sonographic characteristics were analyzed in relation to the histopathological findings. The authors investigated the added value of IOUS in achieving completeness of resection and improving postsurgical seizure outcome. RESULTS The neurosurgeon was able to identify the dysplastic tissue by IOUS in all cases. The visualization of FCD type I was more challenging compared to FCD II and the demarcation of its borders was less clear. Postsurgical MRI showed residual dysplasia in 2 of the 3 patients with FCD type I. In all FCD type II cases, IOUS allowed for a clear intraoperative visualization and demarcation, strongly correlating with presurgical MRI postprocessing. Postsurgical MRI confirmed complete resection in all FCD type II cases. Sonographic features correlated with the histopathological classification of dysplasia (sonographic abnormalities increase continuously in the following order: FCD IA/IB, FCD IC, FCD IIA, FCD IIB). In 1 patient with IOUS features atypical for FCD, histopathological investigation showed nonspecific gliosis. CONCLUSIONS Morphological features of FCD, as identified by IOUS, correlate well with advanced presurgical imaging. The resolution of IOUS was superior to MRI in all FCD types. The appreciation of distinct sonographic features on IOUS allows the intraoperative differentiation between FCD and non-FCD lesions as well as the discrimination of different histological subtypes of FCD. Sonographic demarcation depends on the underlying degree of dysplasia. IOUS allows for more tailored resections by facilitating the delineation of the dysplastic tissue.
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http://dx.doi.org/10.3171/2018.6.FOCUS18221DOI Listing
September 2018

A language-based sum score for the course and therapeutic intervention in primary progressive aphasia.

Alzheimers Res Ther 2018 04 25;10(1):41. Epub 2018 Apr 25.

Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.

Background: With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions.

Methods: We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials.

Results: Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left-sided subcortical structures.

Conclusion: Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies.
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http://dx.doi.org/10.1186/s13195-018-0345-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922300PMC
April 2018

Atrophy in the Thalamus But Not Cerebellum Is Specific for FTD and ALS Patients - An Atlas-Based Volumetric MRI Study.

Front Aging Neurosci 2018 15;10:45. Epub 2018 Mar 15.

Department of Neurology, Ludwig Maximilians Universität München, Munich, Germany.

The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to mutation carriers. This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Atlas-based volumetry was performed in 13 affected FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Our data show that thalamic atrophy in mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating mutation carriers from patients with sporadic FTD.
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http://dx.doi.org/10.3389/fnagi.2018.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863593PMC
March 2018

Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2017 12 8;88(12):1033-1041. Epub 2017 Jun 8.

Faculté de Médecine, INSERM UMR-S1118, Strasbourg, France.

Objective: Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers.

Methods: High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI).

Results: We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (-21.8%, p0.0001) and symptomatic ALS mutation carriers (-13.4%, p<0.001). The atrophy in patients with sporadic ALS was observed in both the anterior (-27.6% p<0.0001) and the posterior parts of the hypothalamus (-17.7%, p<0.0001). Notably, this atrophy was also observed in presymptomatic ALS mutation carriers (-15.5%, p<0.001) and was unrelated to whole brain volume atrophy or disease stage as assessed using DTI or functional status. Hypothalamic volume was correlated with body mass index (BMI) in patients with sporadic ALS (p=0.0434, +0.1579), and this correlation was much stronger in patients with familial ALS (fALS) (p=0.0060, +0.6053). Anterior hypothalamic volume was correlated with age at onset, but not with survival after MRI.

Conclusions: Hypothalamus is atrophied in ALS, even in premorbid stages, and correlates with BMI, especially in fALS. Decreased anterior hypothalamic volume is associated with earlier onset of disease.
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http://dx.doi.org/10.1136/jnnp-2017-315795DOI Listing
December 2017

Reply to: MRI measures of brainstem in parkinsonian syndromes: Where we stand and where we need to go.

Mov Disord 2017 08 7;32(8):1261-1262. Epub 2017 Jun 7.

Department of Neurology, Technische Universität München, Munich, Germany.

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http://dx.doi.org/10.1002/mds.27057DOI Listing
August 2017

Longitudinal magnetic resonance imaging in progressive supranuclear palsy: A new combined score for clinical trials.

Mov Disord 2017 06 24;32(6):842-852. Epub 2017 Apr 24.

Swiss Epilepsy Centre, Klinik Lengg, Zurich, Switzerland.

Background: Two recent, randomized, placebo-controlled phase II/III trials (clinicaltrials.gov: NCT01110720, NCT01049399) of davunetide and tideglusib in progressive supranuclear palsy (PSP) generated prospective, 1-year longitudinal datasets of high-resolution T1-weighted three-dimensional MRI.

Objective: The objective of this study was to develop a quantitative MRI disease progression measurement for clinical trials.

Methods: The authors performed a fully automated quantitative MRI analysis employing atlas-based volumetry and provide sample size calculations based on data collected in 99 PSP patients assigned to placebo in these trials. Based on individual volumes of 44 brain compartments and structures at baseline and 52 weeks of follow-up, means and standard deviations of annualized percentage volume changes were used to estimate standardized effect sizes and the required sample sizes per group for future 2-armed, placebo-controlled therapeutic trials.

Results: The highest standardized effect sizes were found for midbrain, frontal lobes, and the third ventricle. Using the annualized percentage volume change of these structures to detect a 50% change in the 1-year progression (80% power, significance level 5%) required lower numbers of patients per group (third ventricle, n = 32; midbrain, n = 37; frontal lobe, n = 43) than the best clinical scale (PSP rating scale total score, n = 58). A combination of volume changes in these 3 structures reduced the number of required patients to only 20 and correlated best with the progression in the clinical scales.

Conclusions: We propose the 1-year change in the volumes of third ventricle, midbrain, and frontal lobe as combined imaging read-out for clinical trials in PSP that require the least number of patients for detecting efficacy to reduce brain atrophy. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808453PMC
June 2017

Patterns of Eye Movement Impairment Correlate with Regional Brain Atrophy in Neurodegenerative Parkinsonism.

Neurodegener Dis 2017 8;17(4-5):117-126. Epub 2017 Mar 8.

Department of Neurology, University of Ulm, Ulm, Germany.

Background: One common feature of neurodegenerative parkinsonism including Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) is altered eye movement control. Characteristic regional structural atrophy patterns in MRI can be observed in PD, MSA, and PSP.

Objective: To investigate the association between eye movement disturbances and regional brain atrophy in patients with PD, MSA, and PSP.

Methods: High-resolution 3-dimensional T1-weighted MRI images and video-oculographic recordings (EyeLink®) were obtained from 39 PD, 32 PSP, and 18 MSA patients and 24 matched healthy control subjects. Automatic regional volumetric assessment was performed using atlas-based volumetry (ABV).

Results: The prevalence of saccadic intrusions as a measure of inhibitory control was significantly increased in PD patients compared to controls (p < 0.001) and negatively correlated with whole brain volume, cerebral brain volume, and occipital lobe volume (p = 0.0057, p = 0.0049, and p = 0.0059, respectively; all p values are false discovery rate corrected). In MSA, smooth pursuit was disturbed by characteristic "catch-up" saccades (p < 0.001) and it was significantly correlated with cerebellar volume (p = 0.004) and pontine volume (p < 0.001). The hallmark of PSP was pathologically slowed vertical peak eye velocities (p < 0.001); the lower the peak eye velocity, the more marked midbrain atrophy (p = 0.007).

Conclusions: Foci of regional atrophy correlated with disease-specific eye movement alterations in all investigated parkinsonian syndromes. Oculomotor impairment in PD, predominantly the result of executive dysfunction, was linked to cerebral atrophy. Impairment in the corresponding oculomotor pathways was associated with atrophy of pontocerebellar oculomotor structures in MSA and midbrain atrophy in PSP.
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http://dx.doi.org/10.1159/000454880DOI Listing
April 2018

Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias.

Neurology 2017 Mar 8;88(10):961-969. Epub 2017 Feb 8.

From the Department of Neurology (P.S., E.S., S.A.-S., I.U., B.L., C.A.F.v.A., J. Kassubek, P.O., A.C.L., M.O.), University of Ulm; Department of Psychiatry and Psychotherapy (J.D.-S., H.F., C.R.), Technical University of Munich; Clinic for Cognitive Neurology (M.L.S.), University Clinic Leipzig and Max Planck Institute for Human Cognitive and Brain Sciences, Germany; Swiss Epilepsy Center (H.-J.H.), Zürich, Switzerland; Department of Neurology (K. Fassbender), Saarland University, Homburg; Department of Psychiatry and Psychotherapy (K. Fliessbach), University of Bonn and DZNE; Department of Neurology (J.P.), University of Rostock and German Center for Neurodegenerative Diseases; Department of Psychiatry and Psychotherapy (J. Kornhuber), Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen; Department of Psychiatry and Psychotherapy (A.S.), University of Göttingen; Institute of Human Genetics (A.E.V.), University Medical Center Hamburg-Eppendorf, Hamburg; Department of Psychiatry and Psychotherapy (M.L.), University of Würzburg; and Department of Neurology (A.D.), Ludwig-Maximilians-University Munich, Germany.

Objective: To assess the utility of serum neurofilament for diagnosis and monitoring of primary progressive aphasia (PPA) variants.

Methods: We investigated neurofilament light chain (NF-L) levels in blood of 99 patients with PPA (40 with nonfluent variant PPA [nfvPPA], 38 with semantic variant PPA [svPPA], 21 with logopenic variant PPA [lvPPA]) and compared diagnostic performance with that reached by CSF NF-L, phosphorylated neurofilament heavy chain (pNF-H), β-amyloid (Aβ), tau, and phosphorylated tau. The longitudinal change of blood NF-L levels was measured and analyzed for correlation with functional decline and brain atrophy.

Results: Serum NF-L is increased in PPA compared to controls and discriminates between nfvPPA/svPPA and lvPPA with 81% sensitivity and 67% specificity (cutoff 31 pg/mL). CSF NF-L, pNF-H, tau, phosphorylated tau, and Aβ achieved similar performance, and pNF-H was the only marker for discrimination of nfvPPA from svPPA/lvPPA. In most patients with nfvPPA and svPPA, but not lvPPA, serum NF-L increased within follow-up. The increase correlated with functional decline and progression of atrophy of the left frontal lobe of all patients with PPAs and the right middle frontal gyrus of patients with nfvPPA and svPPA.

Conclusions: Blood level of NF-L can aid the differential diagnosis of PPA variants, especially in combination with CSF pNF-H. Because serum NF-L correlates with functional decline and atrophy in the disease course, it qualifies as an objective disease status marker. Extended follow-up studies with cases of known neuropathology are imperative.

Classification Of Evidence: This study provides Class I evidence that in patients with PPA, blood levels of NF-L can distinguish the logopenic variant from the nonfluent/agrammatic and semantic variants.
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http://dx.doi.org/10.1212/WNL.0000000000003688DOI Listing
March 2017

Manual MRI morphometry in Parkinsonian syndromes.

Mov Disord 2017 05 2;32(5):778-782. Epub 2017 Feb 2.

Department of Neurology, Philipps University Marburg, Marburg, Germany.

Background: Several morphometric magnetic resonance imaging parameters may serve for differential diagnosis of parkinsonism. The objective of this study was to identify which performs best in clinical routine.

Methods: We acquired multicentric magnetization-prepared rapid gradient echo sequences in patients with Parkinson's disease (n=204), progressive supranuclear palsy (n=106), multiple system atrophy-cerebellar, (n = 21); multiple system atrophy-parkinsonian (n = 60), and healthy controls (n = 73), performed manual planimetric measurements, and calculated receiver operator characteristics with leave-one-out cross-validation to propose cutoff values.

Results: The midsagittal midbrain area was reduced in PSP versus all other groups (P < 0.001). The midsagittal pons area was reduced in MSA-cerebellar, MSA-parkinsonian, and PSP versus PD patients and healthy controls (P < 0.001). The midbrain/pons area ratio was lower in PSP (P < 0.001) and higher in MSA-cerebellar and MSA-parkinsonian versus PD and PSP (P < 0.001).

Conclusions: The midsagittal midbrain area most reliably identified PSP, the midsagittal pons area MSA-cerebellar. The midbrain/pons area ratio differentiated MSA-cerebellar and PSP better than the magnetic resonance-Parkinson index. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26921DOI Listing
May 2017

Global and regional annual brain volume loss rates in physiological aging.

J Neurol 2017 Mar 4;264(3):520-528. Epub 2017 Jan 4.

Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.

The objective is to estimate average global and regional percentage brain volume loss per year (BVL/year) of the physiologically ageing brain. Two independent, cross-sectional single scanner cohorts of healthy subjects were included. The first cohort (n = 248) was acquired at the Medical Prevention Center (MPCH) in Hamburg, Germany. The second cohort (n = 316) was taken from the Open Access Series of Imaging Studies (OASIS). Brain parenchyma (BP), grey matter (GM), white matter (WM), corpus callosum (CC), and thalamus volumes were calculated. A non-parametric technique was applied to fit the resulting age-volume data. For each age, the BVL/year was derived from the age-volume curves. The resulting BVL/year curves were compared between the two cohorts. For the MPCH cohort, the BVL/year curve of the BP was an increasing function starting from 0.20% at the age of 35 years increasing to 0.52% at 70 years (corresponding values for GM ranged from 0.32 to 0.55%, WM from 0.02 to 0.47%, CC from 0.07 to 0.48%, and thalamus from 0.25 to 0.54%). Mean absolute difference between BVL/year trajectories across the age range of 35-70 years was 0.02% for BP, 0.04% for GM, 0.04% for WM, 0.11% for CC, and 0.02% for the thalamus. Physiological BVL/year rates were remarkably consistent between the two cohorts and independent from the scanner applied. Average BVL/year was clearly age and compartment dependent. These results need to be taken into account when defining cut-off values for pathological annual brain volume loss in disease models, such as multiple sclerosis.
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http://dx.doi.org/10.1007/s00415-016-8374-yDOI Listing
March 2017

Differentiation of neurodegenerative parkinsonian syndromes by volumetric magnetic resonance imaging analysis and support vector machine classification.

Mov Disord 2016 10;31(10):1506-1517

Department of Neurology, University Hospital Gießen and Marburg, Marburg, Germany.

Background: Clinical differentiation of parkinsonian syndromes is still challenging.

Objectives: A fully automated method for quantitative MRI analysis using atlas-based volumetry combined with support vector machine classification was evaluated for differentiation of parkinsonian syndromes in a multicenter study.

Methods: Atlas-based volumetry was performed on MRI data of healthy controls (n = 73) and patients with PD (204), PSP with Richardson's syndrome phenotype (106), MSA of the cerebellar type (21), and MSA of the Parkinsonian type (60), acquired on different scanners. Volumetric results were used as input for support vector machine classification of single subjects with leave-one-out cross-validation.

Results: The largest atrophy compared to controls was found for PSP with Richardson's syndrome phenotype patients in midbrain (-15%), midsagittal midbrain tegmentum plane (-20%), and superior cerebellar peduncles (-13%), for MSA of the cerebellar type in pons (-33%), cerebellum (-23%), and middle cerebellar peduncles (-36%), and for MSA of the parkinsonian type in the putamen (-23%). The majority of binary support vector machine classifications between the groups resulted in balanced accuracies of >80%. With MSA of the cerebellar and parkinsonian type combined in one group, support vector machine classification of PD, PSP and MSA achieved sensitivities of 79% to 87% and specificities of 87% to 96%. Extraction of weighting factors confirmed that midbrain, basal ganglia, and cerebellar peduncles had the largest relevance for classification.

Conclusions: Brain volumetry combined with support vector machine classification allowed for reliable automated differentiation of parkinsonian syndromes on single-patient level even for MRI acquired on different scanners. © 2016 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26715DOI Listing
October 2016

Revised version of quality guidelines for presurgical epilepsy evaluation and surgical epilepsy therapy issued by the Austrian, German, and Swiss working group on presurgical epilepsy diagnosis and operative epilepsy treatment.

Epilepsia 2016 08 29;57(8):1215-20. Epub 2016 Jun 29.

Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt, Germany.

The definition of minimal standards remains pivotal as a basis for a high standard of care and as a basis for staff allocation or reimbursement. Only limited publications are available regarding the required staffing or methodologic expertise in epilepsy centers. The executive board of the working group (WG) on presurgical epilepsy diagnosis and operative epilepsy treatment published the first guidelines in 2000 for Austria, Germany, and Switzerland. In 2014, revised guidelines were published and the WG decided to publish an unaltered English translation in this report. Because epilepsy surgery is an elective procedure, quality standards are particularly high. As detailed in the first edition of these guidelines, quality control relates to seven different domains: (1) establishing centers with a sufficient number of sufficiently and specifically trained personnel, (2) minimum technical standards and equipment, (3) continuous medical education of employees, (4) surveillance by trained personnel during video electroencephalography (EEG) monitoring (VEM), (5) systematic acquisition of clinical and outcome data, (6) the minimum number of preoperative evaluations and epilepsy surgery procedures, and (7) the cooperation of epilepsy centers. These standards required the certification of the different professions involved and minimum numbers of procedures. In the subsequent decade, quite a number of colleagues were certified by the trinational WG; therefore, the executive board of the WG decided in 2013 to make these standards obligatory. This revised version is particularly relevant given that the German procedure classification explicitly refers to the guidelines of the WG with regard to noninvasive/invasive preoperative video-EEG monitoring and invasive intraoperative diagnostics in epilepsy.
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http://dx.doi.org/10.1111/epi.13449DOI Listing
August 2016

Atlas based brain volumetry: How to distinguish regional volume changes due to biological or physiological effects from inherent noise of the methodology.

Magn Reson Imaging 2016 May 23;34(4):455-61. Epub 2015 Dec 23.

Swiss Epilepsy Centre, Zurich, Switzerland.

Fully-automated regional brain volumetry based on structural magnetic resonance imaging (MRI) plays an important role in quantitative neuroimaging. In clinical trials as well as in clinical routine multiple MRIs of individual patients at different time points need to be assessed longitudinally. Measures of inter- and intrascanner variability are crucial to understand the intrinsic variability of the method and to distinguish volume changes due to biological or physiological effects from inherent noise of the methodology. To measure regional brain volumes an atlas based volumetry (ABV) approach was deployed using a highly elastic registration framework and an anatomical atlas in a well-defined template space. We assessed inter- and intrascanner variability of the method in 51 cognitively normal subjects and 27 Alzheimer dementia (AD) patients from the Alzheimer's Disease Neuroimaging Initiative by studying volumetric results of repeated scans for 17 compartments and brain regions. Median percentage volume differences of scan-rescans from the same scanner ranged from 0.24% (whole brain parenchyma in healthy subjects) to 1.73% (occipital lobe white matter in AD), with generally higher differences in AD patients as compared to normal subjects (e.g., 1.01% vs. 0.78% for the hippocampus). Minimum percentage volume differences detectable with an error probability of 5% were in the one-digit percentage range for almost all structures investigated, with most of them being below 5%. Intrascanner variability was independent of magnetic field strength. The median interscanner variability was up to ten times higher than the intrascanner variability.
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http://dx.doi.org/10.1016/j.mri.2015.12.031DOI Listing
May 2016

Morphometric MRI analysis enhances visualization of cortical tubers in tuberous sclerosis.

Epilepsy Res 2015 Nov 8;117:29-34. Epub 2015 Aug 8.

Swiss Epilepsy Centre, Zürich, Switzerland.

Purpose: Focal cortical dysplasias (FCD) type IIb and cortical tubers in tuberous sclerosis complex (TSC) are histopathologically similar and are both epileptogenic lesions frequently causing pharmacoresistant epilepsies. Morphometric analysis of T1- and T2-weighted MRI volume data sets can enhance visualization of FCD. Here, we retrospectively investigated whether morphometric MRI analysis is of equal benefit for visualizing cortical tubers.

Materials And Methods: Morphometric analysis was applied to T1- and partly also T2-weighted 1.5T or 3T MRI volume data sets of 15 TSC patients using a fully automated MATLAB(®) script (i.e. MAP07) commonly used for FCD detection. In this study, focus was on the most sensitive of the resulting morphometric feature maps (i.e. the 'junction image') which highlights blurring of the gray-white matter junction in comparison to a normal database. The visualization of tubers in these 'junction images' was quantitatively compared with that in conventional MR sequences.

Results: In all patients, morphometric analysis visualized almost all tubers detected in the normal MRI, and additionally highlighted on average 23% (range 3-50%) more tubers which were not detected by visual analysis of the conventional MR sequences. When T2 volume data sets from a 3T scanner were available for postprocessing, the rate of additionally detected tubers increased to 29% on average. These formerly overlooked tubers were usually smaller than the tubers already found in the conventional MRI.

Conclusion: Morphometric analysis of MRIs in TSC can highlight cortical tubers which are likely to be overlooked in conventional MRI sequences alone. Additionally detected tubers may be of potential importance for both presurgical evaluation and initial diagnosis of TSC.
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http://dx.doi.org/10.1016/j.eplepsyres.2015.08.002DOI Listing
November 2015

Right fronto-limbic atrophy is associated with reduced empathy in refractory unilateral mesial temporal lobe epilepsy.

Neuropsychologia 2015 Nov 9;78:80-7. Epub 2015 Sep 9.

Swiss Epilepsy Center, Bleulerstrasse 60, 8008 Zürich, Switzerland. Electronic address:

Refractory mesial temporal lobe epilepsy (MTLE) is the most frequent focal epilepsy and is often accompanied by deficits in social cognition including emotion recognition, theory of mind, and empathy. Consistent with the neuronal networks that are crucial for normal social-cognitive processing, these impairments have been associated with functional changes in fronto-temporal regions. However, although atrophy in unilateral MTLE also affects regions of the temporal and frontal lobes that underlie social cognition, little is known about the structural correlates of social-cognitive deficits in refractory MTLE. In the present study, a psychometrically validated empathy questionnaire was combined with whole-brain voxel-based morphometry (VBM) to investigate the relationship between self-reported affective and cognitive empathy and gray matter volume in 55 subjects (13 patients with right MTLE, 9 patients with left MTLE, and 33 healthy controls). Consistent with the brain regions underlying social cognition, our results show that lower affective and cognitive empathy was associated with smaller volume in predominantly right fronto-limbic regions, including the right hippocampus, parahippocampal gyrus, thalamus, fusiform gyrus, inferior temporal gyrus, dorsomedial and dorsolateral prefrontal cortices, and in the bilateral midbrain. The only region that was associated with both affective and cognitive empathy was the right mesial temporal lobe. These findings indicate that patients with right MTLE are at increased risk for reduced empathy towards others' internal states and they shed new light on the structural correlates of impaired social cognition frequently accompanying refractory MTLE. In line with previous evidence from patients with neurodegenerative disease and stroke, the present study suggests that empathy depends upon the integrity of right fronto-limbic and brainstem regions and highlights the importance of the right mesial temporal lobe and midbrain structures for human empathy.
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http://dx.doi.org/10.1016/j.neuropsychologia.2015.09.010DOI Listing
November 2015

Right mesial temporal lobe epilepsy impairs empathy-related brain responses to dynamic fearful faces.

J Neurol 2015 Mar 9;262(3):729-41. Epub 2015 Jan 9.

Swiss Epilepsy Center, Bleulerstrasse 60, 8008, Zurich, Switzerland,

Unilateral mesial temporal lobe epilepsy (MTLE) has been associated with reduced amygdala responsiveness to fearful faces. However, the effect of unilateral MTLE on empathy-related brain responses in extra-amygdalar regions has not been investigated. Using functional magnetic resonance imaging, we measured empathy-related brain responses to dynamic fearful faces in 34 patients with unilateral MTLE (18 right sided), in an epilepsy (extra-MTLE; n = 16) and in a healthy control group (n = 30). The primary finding was that right MTLE (RMTLE) was associated with decreased activity predominantly in the right amygdala and also in bilateral periaqueductal gray (PAG) but normal activity in the right anterior insula. The results of the extra-MTLE group demonstrate that these reduced amygdala and PAG responses go beyond the attenuation caused by antiepileptic and antidepressant medication. These findings clearly indicate that RMTLE affects the function of mesial temporal and midbrain structures that mediate basic interoceptive input necessary for the emotional awareness of empathic experiences of fear. Together with the decreased empathic concern found in the RMTLE group, this study provides neurobehavioral evidence that patients with RMTLE are at increased risk for reduced empathy towards others' internal states and sheds new light on the nature of social-cognitive impairments frequently accompanying MTLE.
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http://dx.doi.org/10.1007/s00415-014-7622-2DOI Listing
March 2015
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