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Background: Diagnostic criteria for progressive supranuclear palsy (PSP) include midbrain atrophy in MRI and hypometabolism in [ 18 F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) as supportive features. Due to limited data regarding their relative and sequential value, there is no recommendation for an algorithm to combine both modalities to increase diagnostic accuracy. This study evaluated the added value of sequential imaging using state-of-the-art methods to analyse the images regarding PSP features., Methods: The retrospective study included 41 PSP patients, 21 with Richardson's syndrome (PSP-RS), 20 with variant PSP phenotypes (vPSP) and 46 sex- and age-matched healthy controls. A pretrained support vector machine (SVM) for the classification of atrophy profiles from automatic MRI volumetry was used to analyse T1w-MRI (output: MRI-SVM-PSP score). Covariance pattern analysis was applied to compute the expression of a predefined PSP-related pattern in FDG-PET (output: PET-PSPRP expression score)., Results: The area under the receiver operating characteristic curve for the detection of PSP did not differ between MRI-SVM-PSP and PET-PSPRP expression score (p≥0.63): about 0.90, 0.95 and 0.85 for detection of all PSP, PSP-RS and vPSP. The MRI-SVM-PSP score achieved about 13% higher specificity and about 15% lower sensitivity than the PET-PSPRP expression score. Decision tree models selected the MRI-SVM-PSP score for the first branching and the PET-PSPRP expression score for a second split of the subgroup with normal MRI-SVM-PSP score, both in the whole sample and when restricted to PSP-RS or vPSP., Conclusions: FDG-PET provides added value for PSP-suspected patients with normal/inconclusive T1w-MRI, regardless of PSP phenotype and the methods to analyse the images for PSP-typical features., Competing Interests: Competing interests: H-JH has used atlas-based volumetric MRI analysis in industry-sponsored research projects. CB received a grant from the Hilde-Ulrichs-Stiftung, served as a consultant for Bial, Hormosan Pharma, Merz Pharmaceuticals and Zambon and received honoraria for scientific presentations from Abbvie, Bial, Stada Pharma, TAD Pharma, UCB Pharma and Zambon. MP-N received lecture fees from Abbott, Abbvie, Boston Scientific and served as consultant for Medtronic, Boston Scientific, Abbott, Zambon and Abbvie. SK was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy–ID 390857198), the Ehrmann Foundation and the Lüneburg Heritage. SK receives research funding from CurePSP and reports travel support from Life Molecular Imaging outside the submitted work. MK received honoraria for scientific presentations from Abbvie and Ever Pharma. JL reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer medical publishers and is inventor in a patent 'Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies' (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG, is beneficiary of the phantom share program of MODAG and is inventor in a patent 'Pharmaceutical Composition and Methods of Use' (EP 22 159 408.8) filed by MODAG, all activities outside the submitted work. J-JR received speaker honoraria from GE Healthcare. OS received research support from Life Molecular Imaging. HB received reader honoraria from Life Molecular Imaging and speaker honoraria from Novartis/AAA. MPW received speaker or consultancy honoraria from Alexion, Bayer Healthcare, Biogen, Biologix, Bristol Myers Squibb, Celgene, Genilac, Imcyse, IXICO, Icometrix, Medison, Merck-Serono, Novartis, Roche, Sanofi-Genzyme. Publication royalties from Springer and Elsevier. GH was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy–ID 390857198) and within the Hannover Cluster RESIST (EXC 2155–project number 39087428), the EU/EFPIA/Innovative Medicines Initiative (2) Joint Undertaking (IMPRIND grant no 116060), the European Joint Programme on Rare Diseases (Improve-PSP), Deutsche Forschungsgemeinschaft (DFG, HO2402/6-2 Heisenberg Program, HO2402/18-1 MSAomics), the VolkswagenStiftung (Niedersächsisches Vorab), the Petermax-Müller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies); participated in indurtry-sponsored research projects from Abbvie, Biogen, Biohaven, Novartis, Roche, Sanofi, UCB; served as a consultant for Abbvie, Alzprotect, Aprineua, Asceneuron, Bial, Biogen, Biohaven, Kyowa Kirin, Lundbeck, Novartis, Retrotope, Roche, Sanofi, UCB; received honoraria for scientific presentations from Abbvie, Bayer Vital, Bial, Biogen, Bristol Myers Squibb, Kyowa Kirin, Roche, Teva, UCB, Zambon; received publication royalties from Academic Press, Kohlhammer and Thieme. All other authors declare that they have no potential conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed., Objective: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials., Methods: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data., Results: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems., Conclusions: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging., Methods: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry., Results: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta 1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects., Discussion: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy., Highlights: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis., Methods: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm 3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level., Results: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients., Significance: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The absence of MRI-lesion reduces considerably the probability of having an excellent outcome (International League Against Epilepsies [ILAE] class I-II) after epilepsy surgery. Surgical success in magnetic-resonance imaging (MRI)-negative cases relies therefore mainly on non-invasive techniques such as positron-emission tomography (PET), subtraction ictal/inter-ictal single-photon-emission-computed-tomography co-registered to MRI (SISCOM), electric source imaging (ESI) and morphometric MRI analysis (MAP). We were interested in identifying the optimal imaging technique or combination to achieve post-operative class I-II in patients with MRI-negative focal epilepsy., Methods: We identified 168 epileptic patients without MRI lesion. Thirty-three (19.6%) were diagnosed with unifocal epilepsy, underwent surgical resection and follow-up ⩾ 2 years. Sensitivity, specificity, predictive values, and diagnostic odds ratio (OR) were calculated for each technique individually and in combination (after co-registration)., Results: 23/33 (70%) were free of disabling seizures (75.0% with temporal and 61.5% extratemporal lobe epilepsy). None of the individual modalities presented an OR > 1.5, except ESI if only patients with interictal epileptiform discharges (IEDs) were considered (OR 3.2). On a dual combination, SISCOM with ESI presented the highest outcome (OR = 6). MAP contributed to detecting indistinguishable focal cortical dysplasia in particular in extratemporal epilepsies with a sensitivity of 75%. Concordance of PET, ESI on interictal epileptic discharges, and SISCOM was associated with the highest chance for post-operative seizure control (OR = 11)., Conclusion: If MRI is negative, the chances to benefit from epilepsy surgery are almost as high as in lesional epilepsy, provided that multiple established non-invasive imaging tools are rigorously applied and co-registered together., (© 2023. The Author(s).)

Background: To date, studies on positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP-RS)., Objectives: To evaluate FDG-PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice., Methods: This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non-RS variants of PSP (vPSP), and 46 age-matched healthy controls. Two state-of-the art methods for the interpretation of FDG-PET were compared: visual analysis supported by voxel-based statistical testing (five readers) and automatic covariance pattern analysis using a predefined PSP-related pattern., Results: Sensitivity and specificity of the majority visual read for the detection of PSP in the whole cohort were 74% and 72%, respectively. The percentage of false-negative cases was 10% in the PSP-RS subsample and 43% in the vPSP subsample. Automatic covariance pattern analysis provided sensitivity and specificity of 93% and 83% in the whole cohort. The percentage of false-negative cases was 0% in the PSP-RS subsample and 15% in the vPSP subsample., Conclusions: Visual interpretation of FDG-PET supported by voxel-based testing provides good accuracy for the detection of PSP-RS, but only fair sensitivity for vPSP. Automatic covariance pattern analysis outperforms visual interpretation in the detection of PSP-RS, provides clinically useful sensitivity for vPSP, and reduces the rate of false-positive findings. Thus, pattern expression analysis is clinically useful to complement visual reading and voxel-based testing of FDG-PET in suspected PSP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Brain magnetic resonance imaging (MRI) is used to support the diagnosis of progressive supranuclear palsy (PSP). However, the value of visual descriptive, manual planimetric, automatic volumetric MRI markers and fully automatic categorization is unclear, particularly regarding PSP predominance types other than Richardson's syndrome (RS)., Objectives: To compare different visual reading strategies and automatic classification of T1-weighted MRI for detection of PSP in a typical clinical cohort including PSP-RS and (non-RS) variant PSP (vPSP) patients., Methods: Forty-one patients (21 RS, 20 vPSP) and 46 healthy controls were included. Three readers using three strategies performed MRI analysis: exclusively visual reading using descriptive signs (hummingbird, morning-glory, Mickey-Mouse), visual reading supported by manual planimetry measures, and visual reading supported by automatic volumetry. Fully automatic classification was performed using a pre-trained support vector machine (SVM) on the results of atlas-based volumetry., Results: All tested methods achieved higher specificity than sensitivity. Limited sensitivity was driven to large extent by false negative vPSP cases. Support by automatic volumetry resulted in the highest accuracy (75.1% ± 3.5%) among the visual strategies, but performed not better than the midbrain area (75.9%), the best single planimetric measure. Automatic classification by SVM clearly outperformed all other methods (accuracy, 87.4%), representing the only method to provide clinically useful sensitivity also in vPSP (70.0%)., Conclusions: Fully automatic classification of volumetric MRI measures using machine learning methods outperforms visual MRI analysis without and with planimetry or volumetry support, particularly regarding diagnosis of vPSP, suggesting the use in settings with a broad phenotypic PSP spectrum. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Phelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood. Since symptoms of the autism spectrum, regression, and stagnation in development occur, we investigated whether neuroinflammatory and neurodegenerative processes may also play a role. To this end, we analysed biomarkers in cerebrospinal fluid (CSF) and parameters from magnetic resonance imaging with high-resolution structural T1w volumetry and diffusion tensor imaging analysis in 19 Phelan-McDermid syndrome patients., Results: CSF showed no inflammation but abnormalities in tau protein and amyloid-ß concentrations, however, with no typical biomarker pattern as in Alzheimer's disease. It could be demonstrated that these CSF changes were correlated with integrity losses of the fibres in the corticospinal tract as well as in the splenium and dorsal part of the cingulum. High CSF levels of tau protein were associated with loss of integrity of fibres in the corticospinal tract; lower levels of amyloid-ß were associated with decreasing integrity of fibre tracts of the splenium and posterior cingulate gyrus. Volumetric investigations showed global atrophy of the white matter, but not the grey matter, and particularly not in temporal or mesiotemporal regions, as is typical in later stages of Alzheimer's disease., Conclusions: In summary, alterations of neurodegenerative CSF markers in PMS individuals could be demonstrated which were correlated with structural connectivity losses of the corticospinal tract, the splenium, and the dorsal part of the cingulum, which can also be associated with typical clinical symptoms in these patients. These findings might represent a state of dysfunctional processes with ongoing degenerative and regenerative processes or a kind of accelerated aging. This study should foster further clinical diagnostics like tau- and amyloid-PET imaging as well as novel scientific approaches especially in basic research for further mechanistic proof., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Purpose: To evaluate the diagnostic accuracy of epilepsy-dedicated 3 Tesla MRI including post-processing by correlating MRI, histopathology, and postsurgical seizure outcomes., Methods: 3 Tesla-MRI including a magnetization-prepared two rapid acquisition gradient echo (MP2RAGE) sequence for post-processing using the morphometric analysis program MAP was acquired in 116 consecutive patients with drug-resistant focal epilepsy undergoing resection surgery. The MRI, histopathology reports and postsurgical seizure outcomes were recorded from the patient's charts., Results: The MRI and histopathology were concordant in 101 and discordant in 15 patients, 3 no hippocampal sclerosis/gliosis only lesions were missed on MRI and 1 of 28 focal cortical dysplasia (FCD) type II associated with a glial scar was considered a glial scar only on MRI. In another five patients, MRI was suggestive of FCD, the histopathology was uneventful but patients were seizure-free following surgery. The MRI and histopathology were concordant in 20 of 21 glioneuronal tumors, 6 cavernomas, and 7 glial scars. Histopathology was negative in 10 patients with temporal lobe epilepsy, 4 of them had anteroinferior meningoencephaloceles. Engel class IA outcome was reached in 71% of patients., Conclusion: The proposed MRI protocol is highly accurate. No hippocampal sclerosis/gliosis only lesions are typically MRI negative. Small MRI positive FCD can be histopathologically missed, most likely due to sampling errors resulting from insufficient harvesting of tissue., (© 2023. The Author(s).)

Hippocampal volumetry is an essential tool in researching and diagnosing mesial temporal lobe epilepsy (mTLE). However, it has a limited ability to detect subtle alterations in hippocampal morphometry. Here, we establish and apply a novel geometry-based tool that enables point-wise morphometric analysis based on an intrinsic coordinate system of the hippocampus. We hypothesized that this point-wise analysis uncovers structural alterations not measurable by volumetry, but associated with histological underpinnings and the neuropsychological profile of mTLE. We conducted a retrospective study in 204 individuals with mTLE and 57 age- and gender-matched healthy subjects. FreeSurfer-based segmentations of hippocampal subfields in 3T-MRI were subjected to a geometry-based analysis that resulted in a coordinate system of the hippocampal mid-surface and allowed for point-wise measurements of hippocampal thickness and other features. Using point-wise analysis, we found significantly lower thickness and higher FLAIR signal intensity in the entire affected hippocampus of individuals with hippocampal sclerosis (HS-mTLE). In the contralateral hippocampus of HS-mTLE and the affected hippocampus of MRI-negative mTLE, we observed significantly lower thickness in the presubiculum. Impaired verbal memory was associated with lower thickness in the left presubiculum. In HS-mTLE histological subtype 3, we observed higher curvature than in subtypes 1 and 2 (all p < .05). These findings could not be observed using conventional volumetry (Bonferroni-corrected p < .05). We show that point-wise measures of hippocampal morphometry can uncover structural alterations not measurable by volumetry while also reflecting histological underpinnings and verbal memory. This substantiates the prospect of their clinical application., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common pathologies causing pharmacoresistant focal epilepsy. Resective neurosurgery yields high success rates, especially if the full extent of the lesion is correctly identified and completely removed. The visual assessment of magnetic resonance imaging does not pinpoint the FCD in 30%-50% of cases, and half of all patients with FCD are not amenable to epilepsy surgery, partly because the FCD could not be sufficiently localized. Computational approaches to FCD detection are an active area of research, benefitting from advancements in computer vision. Automatic FCD detection is a significant challenge and one of the first clinical grounds where the application of artificial intelligence may translate into an advance for patients' health. The emergence of new methods from the combination of health and computer sciences creates novel challenges. Imaging data need to be organized into structured, well-annotated datasets and combined with other clinical information, such as histopathological subtypes or neuroimaging characteristics. Algorithmic output, that is, model prediction, requires a technically correct evaluation with adequate metrics that are understandable and usable for clinicians. Publication of code and data is necessary to make research accessible and reproducible. This critical review introduces the field of automatic FCD detection, explaining underlying medical and technical concepts, highlighting its challenges and current limitations, and providing a perspective for a novel research environment., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD)., Methods: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores., Results: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy., Discussion: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations., Highlights: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL)., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Dementia syndromes can be difficult to diagnose. We aimed at building a classifier for multiple dementia syndromes using magnetic resonance imaging (MRI)., Methods: Atlas-based volumetry was performed on T1-weighted MRI data of 426 patients and 51 controls from the multi-centric German Research Consortium of Frontotemporal Lobar Degeneration including patients with behavioral variant frontotemporal dementia, Alzheimer's disease, the three subtypes of primary progressive aphasia, i.e., semantic, logopenic and nonfluent-agrammatic variant, and the atypical parkinsonian syndromes progressive supranuclear palsy and corticobasal syndrome. Support vector machine classification was used to classify each patient group against controls (binary classification) and all seven diagnostic groups against each other in a multi-syndrome classifier (multiclass classification)., Results: The binary classification models reached high prediction accuracies between 71 and 95% with a chance level of 50%. Feature importance reflected disease-specific atrophy patterns. The multi-syndrome model reached accuracies of more than three times higher than chance level but was far from 100%. Multi-syndrome model performance was not homogenous across dementia syndromes, with better performance in syndromes characterized by regionally specific atrophy patterns. Whereas diseases generally could be classified vs controls more correctly with increasing severity and duration, differentiation between diseases was optimal in disease-specific windows of severity and duration., Discussion: Results suggest that automated methods applied to MR imaging data can support physicians in diagnosis of dementia syndromes. It is particularly relevant for orphan diseases beside frequent syndromes such as Alzheimer's disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: ALS patients with hexanucleotide expansion in C9orf72 are characterized by a specific clinical phenotype, including more aggressive disease course and cognitive decline. Computerized multiparametric MRI with gray matter volumetry and diffusion tensor imaging (DTI) to analyze white matter structural connectivity is a potential in vivo biomarker., Objective: The objective of this study was to develop a multiparametric MRI signature in a large cohort of ALS patients with C9orf72 mutations. The aim was to investigate how morphological features of C9orf72-associated ALS differ in structural MRI and DTI compared to healthy controls and ALS patients without C9orf72 mutations., Methods: Atlas-based volumetry (ABV) and whole brain-based DTI-based analyses were performed in a cohort of n = 51 ALS patients with C9orf72 mutations and compared with both n = 51 matched healthy controls and n = 51 C9orf72 negative ALS patients, respectively. Subsequently, Spearman correlation analysis of C9orf72 ALS patients' data with clinical parameters (age of onset, sex, ALS-FRS-R, progression rate, survival) as well as ECAS and p-NfH in CSF was performed., Results: The whole brain voxel-by-voxel comparison of fractional anisotropy (FA) maps between C9orf72 ALS patients and controls showed significant bilateral alterations in axonal structures of the white matter at group level, primarily along the corticospinal tracts and in fibers projecting to the frontal lobes. For the frontal lobes, these alterations were also significant between C9orf72 positive and C9orf72 negative ALS patients. In ABV, patients with C9orf72 mutations showed lower volumes of the frontal, temporal, and parietal lobe, with the lowest values in the gray matter of the superior frontal and the precentral gyrus, but also in hippocampi and amygdala. Compared to C9orf72 negative ALS, the differences were shown to be significant for cerebral gray matter (p = 0.04), especially in the frontal (p = 0.01) and parietal lobe (p = 0.01), and in the thalamus (p = 0.004). A correlation analysis between ECAS and averaged regional FA values revealed significant correlations between cognitive performance in ECAS and frontal association fibers. Lower FA values in the frontal lobes were associated with worse performance in all cognitive domains measured (language, verbal fluency, executive functions, memory and spatial perception). In addition, there were significant negative correlations between age of onset and atlas-based volumetry results for gray matter., Conclusions: This study demonstrates a distinct pattern of DTI alterations of the white matter and ubiquitous volume reductions of the gray matter early in the disease course of C9orf72-associated ALS. Alterations were closely linked to a more aggressive cognitive phenotype. These results are in line with an expected pTDP43 propagation pattern of cortical affection and thus strengthen the hypothesis that an underlying developmental disorder is present in ALS with C9orf72 expansions. Thus, multiparametric MRI could contribute to the assessment of the disease as an in vivo biomarker even in the early phase of the disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context., Objective: Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging., Design, Setting, and Participants: Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes., Interventions: N.A., Main Outcomes and Measures: Cohen's kappa, accuracy, and F1-score to assess model performance., Results: Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy., Conclusions and Relevance: Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best., (© 2022. The Author(s).)

Background: Flail arm syndrome is a restricted phenotype of motor neuron disease that is characterized by progressive, predominantly proximal weakness and atrophy of the upper limbs., Objective: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from flail arm syndrome patients using a hypothesis-guided tract-of-interest-based approach to identify in vivo microstructural changes according to a neuropathologically defined amyotrophic lateral sclerosis (ALS)-related pathology of the cortico-efferent tracts., Methods: DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the neuropathological ALS-propagation pattern for 43 flail arm syndrome patients vs 43 'classical' ALS patients vs 40 matched controls., Results: The analysis of white matter integrity demonstrated regional FA reductions for the flail arm syndrome group predominantly along the CST. In the tract-specific analysis according to the proposed sequential cerebral pathology pattern of ALS, the flail arm syndrome patients showed significant alterations of the specific tract systems that were identical to 'classical' ALS if compared to controls., Conclusions: The DTI study including the tract-of-interest-based analysis showed a microstructural involvement pattern in the brains of flail arm syndrome patients, supporting the hypothesis that flail arm syndrome is a phenotypical variant of ALS., (© 2021. The Author(s).)

Purpose: To evaluate a MRI postprocessing tool for the enhanced and rapid detection of focal cortical dysplasia (FCD)., Methods: MP2RAGE sequences of 40 consecutive, so far MRI-negative patients and of 32 healthy controls were morphometrically analyzed to highlight typical FCD features. The resulting morphometric maps served as input for an artificial neural network generating a FCD probability map. The FCD probability map was inversely normalized, co-registered to the MPRAGE2 sequence, and re-transferred into the PACS system. Co-registered images were scrolled through "within a minute" to determine whether a FCD was present or not., Results: Fifteen FCD, three subcortical band heterotopias (SBH), and one periventricular nodular heterotopia were identified. Of those, four FCD and one SBH were only detected by MRI postprocessing while one FCD and one focal polymicrogryia were missed, respectively. False-positive results occurred in 21 patients and 22 healthy controls. However, true positive cluster volumes were significantly larger than volumes of false-positive clusters (p < 0.001). The area under the curve of the receiver operating curve was 0.851 with a cut-off volume of 0.05 ml best indicating a FCD., Conclusion: Automated MRI postprocessing and presentation of co-registered output maps in the PACS allowed for rapid (i.e., "within a minute") identification of FCDs in our clinical setting. The presence of false-positive findings currently requires a careful comparison of postprocessing results with conventional MR images but may be reduced in the future using a neural network better adapted to MP2RAGE images., (© 2022. The Author(s).)

Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in ASPM leading to a truncation of the ASPM protein after amino acid position 1830. The phenotype of the patients was associated with microcephaly, epilepsy, and behavioral and cognitive deficits. Despite the obvious genetic similarity, the affected patients show a considerable phenotypic heterogeneity regarding the degree of mental retardation, presence of epilepsy and MRI findings. Interestingly, the degree of mental retardation and the presence of epilepsy correlates well with the severity of abnormalities detected in brain MRI. On the other hand, we detected no evidence for substantial nonsense-mediated ASPM transcript decay in blood samples. This indicates that other factors than ASPM expression levels are relevant for the variability of structural changes in brain morphology seen in patients with primary hereditary microcephaly caused by ASPM mutations.

Background: Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa-responsive dystonia (DRD). Diagnosis and treatment are often delayed due to high between- and within-group variability., Objectives: Comprehensively analyzed individual genotype, phenotype, treatment response, and biochemistry information., Methods: 734 DRD patients and 151 asymptomatic GCH1 mutation carriers were included using an MDSGene systematic literature review and an automated classification approach to distinguish between different forms of monogenic DRDs., Results: Whereas dystonia, L-Dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags, parkinsonism without dystonia was rarely reported (11%) and combined with dystonia in only 18% of patients. While sex was equally distributed in autosomal recessive DRD, there was female predominance in autosomal dominant DYT/PARK-GCH1 patients accompanied by a lower median age at onset and more dystonia in females compared to males. Accordingly, the majority of asymptomatic heterozygous GCH1 mutation carriers (>8 years of age) were males. Multiple other subgroup-specific characteristics were identified, showing high accuracy in the automated classification approach: Seizures and microcephaly were mostly seen in DYT/PARK-PTS, autonomic symptoms appeared commonly in DYT/PARK-TH and DYT/PARK-PTS, and sleep disorders and oculogyric crises in DYT/PARK-SPR. Biochemically, homovanillic acid and 5-hydroxyindoleacetic acid in CSF were reduced in most DRDs, but neopterin and biopterin were increased only in DYT/PARK-PTS and DYT/PARK-SPR. Hyperphenylalaninemia was seen in DYT/PARK-PTS, DYT/PARK-QDPR, and rarely reported in autosomal recessive DYT/PARK-GCH1., Conclusions: Our indicators will help to specify diagnosis and accelerate start of treatment. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: The detection of focal cortical dysplasia (FCD) in magnetic resonance imaging is challenging. Voxel-based morphometric analysis and automated FCD detection using an artificial neural network (ANN) integrated into the Morphometric Analysis Program (MAP18) have been shown to facilitate FCD detection. This study aimed to evaluate whether the detection of FCD can be further improved by feeding this approach with magnetization prepared two rapid acquisition gradient echoes (MP2RAGE) instead of magnetization-prepared rapid acquisition gradient echo (MPRAGE) datasets., Methods: MPRAGE and MP2RAGE datasets were acquired in a consecutive sample of 32 patients with FCD and postprocessed using MAP18. Visual analysis and, if available, histopathology served as the gold standard for assessing the sensitivity and specificity of FCD detection. Out-of-sample specificity was evaluated in a cohort of 32 healthy controls., Results: The sensitivity and specificity of FCD detection were 82.4% and 62.5% for the MPRAGE and 97.1% and 34.4% for the MP2RAGE sequences, respectively. Median volumes of true-positive voxel clusters were .16 ml for the MPRAGE and .52 ml for the MP2RAGE sequences compared to .08- and .04-ml volumes of false-positive clusters. With regard to cluster volumes, FCD detection was substantially improved for the MP2RAGE data when the estimated optimal threshold of .23 ml was applied (sensitivity = 72.9%, specificity = 83.0%). In contrast, the estimated optimal threshold of .37 ml for the MPRAGE data did not improve FCD lesion detection (sensitivity = 42.9%, specificity = 79.5%)., Significance: In this study, the sensitivity of FCD detection by morphometric analysis and an ANN integrated into MAP18 was higher for MP2RAGE than for MPRAGE sequences. Additional usage of cluster volume information helped to discriminate between true- and false-positive MP2RAGE results., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: The behavioral variant of frontotemporal dementia (bvFTD) is a rare neurodegenerative disease. Reliable predictors of disease progression have not been sufficiently identified. We investigated multivariate magnetic resonance imaging (MRI) biomarker profiles for their predictive value of individual decline., Methods: One hundred five bvFTD patients were recruited from the German frontotemporal lobar degeneration (FTLD) consortium study. After defining two groups ("fast progressors" vs. "slow progressors"), we investigated the predictive value of MR brain volumes for disease progression rates performing exhaustive screenings with multivariate classification models., Results: We identified areas that predict disease progression rate within 1 year. Prediction measures revealed an overall accuracy of 80% across our 50 top classification models. Especially the pallidum, middle temporal gyrus, inferior frontal gyrus, cingulate gyrus, middle orbitofrontal gyrus, and insula occurred in these models., Discussion: Based on the revealed marker combinations an individual prognosis seems to be feasible. This might be used in clinical studies on an individualized progression model., Competing Interests: The authors declare no conflicts of interest., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that, especially in the early stages of the disease, is clinically difficult to distinguish from Parkinson's disease (PD). Objective: This study aimed at assessing the use of eye-tracking in head-mounted displays (HMDs) for differentiating PSP and PD. Methods: Saccadic eye movements of 13 patients with PSP, 15 patients with PD, and a group of 16 healthy controls (HCs) were measured. To improve applicability in an inpatient setting and standardize the diagnosis, all the tests were conducted in a HMD. In addition, patients underwent atlas-based volumetric analysis of various brain regions based on high-resolution MRI. Results: Patients with PSP displayed unique abnormalities in vertical saccade velocity and saccade gain, while horizontal saccades were less affected. A novel diagnostic index was derived, multiplying the ratios of vertical to horizontal gain and velocity, allowing segregation of PSP from PD with high sensitivity (10/13, 77%) and specificity (14/15, 93%). As expected, patients with PSP as compared with patients with PD showed regional atrophy in midbrain volume, the midbrain plane, and the midbrain tegmentum plane. In addition, we found for the first time that oculomotor measures (vertical gain, velocity, and the diagnostic index) were correlated significantly to midbrain volume in the PSP group. Conclusions: Assessing eye movements in a HMD provides an easy to apply and highly standardized tool to differentiate PSP of patients from PD and HCs, which will aid in the diagnosis of PSP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Herwig, Agic, Huppertz, Klingebiel, Zuhorn, Schneider, Schäbitz and Rogalewski.)

Background: The regional distribution of the widespread cerebral morphological alterations in progressive supranuclear palsy (PSP) is considered to include segmental parts of the corpus callosum (CC). Objective: The study was designed to investigate the regional white matter (WM) of the CC by T1 weighted magnetic resonance imaging (T1w MRI) data combined with diffusion tensor imaging (DTI) data in PSP patients, differentiated in the variants Richardson syndrome and PSP-parkinsonism, and to compare them with Parkinson's Disease (PD) patients and healthy controls, in order to identify macro- and micro-structural alterations in vivo . Methods: MRI-based WM mapping was used to perform an operator-independent segmentation for the different CC segments in 66 PSP patients vs. 66 PD patients vs. 44 matched healthy controls. The segmentation was followed by both planimetric and texture analysis of the separated CC areas for the comparison of the three groups. Results were complemented by a DTI-based tract-of-interest analysis of the associated callosal tracts. Results: Significant alterations of the parameters entropy and homogeneity compared to controls were observed for PSP as well as for PD for the CC areas I, II, and III. The inhomogeneity in area II in the PSP cohort was the highest and differed significantly from PD. A combined score was defined as a potential marker for the different types of neurodegenerative parkinsonism; receiver operating characteristics (ROC) curves were calculated with areas under the curve values of 0.86 for PSP vs. controls, 0.72 for PD vs. controls, and 0.69 for PSP vs. PD, respectively. Conclusion: The multiparametric MRI texture and DTI analysis demonstrated extensive alterations of the frontal CC in neurodegenerative parkinsonism, whereas regional CC atrophy cannot be regarded as a constant neuroimaging feature of PSP. Specifically, the comparison PSP vs. PD revealed significant alterations in callosal area II. The combination of the texture and the DTI parameters might contribute as a neuroimaging marker for the assessment of the CC in PSP, including the differentiation vs. PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bârlescu, Müller, Uttner, Ludolph, Pinkhardt, Huppertz and Kassubek.)

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., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Müller, Behler, Landwehrmeyer, Huppertz and Kassubek.)

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 -12 ) 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., (© 2021 International Parkinson and Movement Disorder Society.)

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.

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., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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.

Background and Purpose: Focal cortical dysplasias are the most common resected epileptogenic lesions in children and the third most common lesion in adults, but they are often subtle and frequently overlooked on MR imaging. The purpose of this study was to evaluate whether MP2RAGE-based morphometric MR imaging analysis is superior to MPRAGE-based analysis in the detection of focal cortical dysplasia., Materials and Methods: MPRAGE and MP2RAGE datasets were acquired in a consecutive series of 640 patients with epilepsy. Datasets were postprocessed using the Morphometric Analysis Program to generate morphometric z score maps such as junction, extension, and thickness images based on both MPRAGE and MP2RAGE images. Focal cortical dysplasia lesions were manually segmented in the junction images, and volumes and mean z scores of the lesions were measured., Results: Of 21 focal cortical dysplasias discovered, all were clearly visible on MP2RAGE junction images, whereas 2 were not visible on MPRAGE junction images. In all except 4 patients, the volume of the focal cortical dysplasia was larger and mean lesion z scores were higher on MP2RAGE junction images compared with the MPRAGE-based images ( P  = .005, P  = .013)., Conclusions: In this study, MP2RAGE-based morphometric analysis created clearer output maps with larger lesion volumes and higher z scores than the MPRAGE-based analysis. This new approach may improve the detection of subtle, otherwise overlooked focal cortical dysplasia., (© 2020 by American Journal of Neuroradiology.)

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., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Objective: Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan-McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function., Methods and Results: Diffusion tensor imaging-based and automatic volumetric brain mapping were performed in 12 SHANK3-deficient participants (mean age 19 ± 15 years) versus 14 age- and gender-matched controls (mean age 29 ± 5 years). Using whole brain-based spatial statistics, we observed a highly significant pattern of white matter alterations in participants with SHANK3 mutations with focus on the long association fiber tracts, particularly the uncinate tract and the inferior fronto-occipital fasciculus. In contrast, only subtle gray matter volumetric abnormalities were detectable. In a back-translational approach, we observed similar white matter alterations in heterozygous isoform-specific Shank3 knockout (KO) mice. Here, in the baseline data sets, the comparison of Shank3 heterozygous KO vs wildtype showed significant fractional anisotropy reduction of the long fiber tract systems in the KO model. The multiparametric Magnetic Resonance Imaging (MRI) analysis by DTI and volumetry demonstrated a pathology pattern with severe white matter alterations and only subtle gray matter changes in the animal model., Interpretation: In summary, these translational data provide strong evidence that the SHANK3-deficiency-associated pathomechanism presents predominantly with a white matter disease. Further studies should concentrate on the role of SHANK3 during early axonal pathfinding/wiring and in myelin formation., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

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., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

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 r = 0.706, p < 0.0001; AD/MCI r = 0.666, p = 0.0003). Highest serum levels were observed in bvFTD ( p <0 0.0001 vs Con and MCI, p = 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 ( p = 0.0039 and p = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] r = 0.4157, p = 0.0006; [follow-up] r = 0.5629, p < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: r = -0.5857, p < 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] r = 0.6624, p < 0.0001; [follow-up] r = 0.5659, p = 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., (© 2018 American Academy of Neurology.)

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.