Publications by authors named "Alexander U Brandt"

154 Publications

AQP4-IgG autoimmunity in Japan and Germany: Differences in clinical profiles and prognosis in seropositive neuromyelitis optica spectrum disorders.

Mult Scler J Exp Transl Clin 2021 Apr-Jun;7(2):20552173211006862. Epub 2021 May 4.

Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, and Charite - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Background: Clinical outcomes in neuromyelitis optica spectrum disorders (NMOSD) vary across different regions.

Objective: To describe clinical profiles in Japanese and German NMOSD patients.

Methods: Medical records of aquaporin-4-immunoglobulin G (AQP4-IgG) positive NMOSD patients from Japan (n = 54) and Germany (n = 38) were retrospectively analyzed.

Results: The disability status was similar between both cohorts, although Japanese patients had a longer disease duration (13.3 ± 11.1 vs. 8.1 ± 6.9 years, p = 0.018) but similar relapse rates. Optic neuritis and myelitis were the most frequent attacks in both cohorts. Brain attacks occurred more frequently in Japanese patients (40.7% vs. 15.8%, p = 0.020). The time from disease onset (median [interquartile range] 2.3 [0.3-10.1] vs. 0.6 [0.2-1.9] years, p = 0.009) and the number of attacks (2.5 [1-7] vs. 2 [1-3], p = 0.047) until start of the first immunotherapy were higher in the Japanese cohort. Rituximab was the most common drug in the German cohort (52.6%) and not given in the Japanese cohort (p < 0.001), where oral prednisolone was the most common drug (92.6% vs. 15.8%, p < 0.001). The frequency of autoimmune comorbidities was higher in the German cohort (39.5% vs. 18.5%, p = 0.047).

Conclusion: Compared with Japanese NMOSD patients, German patients presented with similar disability despite shorter disease duration and earlier and more frequent immunosuppressive therapy.
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http://dx.doi.org/10.1177/20552173211006862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114278PMC
May 2021

Artificial intelligence extension of the OSCAR-IB criteria.

Ann Clin Transl Neurol 2021 May 19. Epub 2021 May 19.

Division of Neurology, Department of Pediatrics, Hospital for Sick Children, Division of Neurosciences and Mental Health SickKids Research Institute, University of Toronto, Canada.

Artificial intelligence (AI)-based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human-led validated consensus quality control criteria (OSCAR-IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI-based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five-point expansion of the OSCAR-IB criteria to embrace AI (OSCAR-AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.
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http://dx.doi.org/10.1002/acn3.51320DOI Listing
May 2021

Retinal Thickness Analysis in Progressive Multiple Sclerosis Patients Treated With Epigallocatechin Gallate: Optical Coherence Tomography Results From the SUPREMES Study.

Front Neurol 2021 28;12:615790. Epub 2021 Apr 28.

Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Epigallocatechin gallate (EGCG) is an anti-inflammatory agent and has proven neuroprotective properties in animal models of multiple sclerosis (MS). Optical coherence tomography (OCT) assessed retinal thickness analysis can reflect treatment responses in MS. To analyze the influence of EGCG treatment on retinal thickness analysis as secondary and exploratory outcomes of the randomized controlled trial (SUPREMES, NCT00799890). SUPREMES patients underwent OCT with the Heidelberg Spectralis device at a subset of visits. We determined peripapillary retinal nerve fiber layer (pRNFL) thickness from a 12° ring scan around the optic nerve head and thickness of the ganglion cell/inner plexiform layer (GCIP) and inner nuclear layer (INL) within a 6 mm diameter grid centered on the fovea from a macular volume scan. Longitudinal OCT data were available for exploratory analysis from 31 SUPREMES participants (12/19 primary/secondary progressive MS (PPMS/SPMS); mean age 51 ± 7 years; 12 female; mean time since disease onset 16 ± 11 years). We tested the null hypothesis of no treatmenttime interaction using nonparametric analysis of longitudinal data in factorial experiments. After 2 years, there were no significant differences in longitudinal retinal thickness changes between EGCG treated and placebo arms in any OCT parameter (Mean change [confidence interval] ECGC vs. Placebo: pRNFL: -0.83 [1.29] μm vs. -0.64 [1.56] μm, = 0.156; GCIP: -0.67 [0.67] μm vs. -0.14 [0.47] μm, = 0.476; INL: -0.06 [0.58] μm vs. 0.22 [0.41] μm, = 0.455). Retinal thickness analysis did not reveal a neuroprotective effect of EGCG. While this is in line with the results of the main SUPREMES trial, our study was probably underpowered to detect an effect. www.ClinicalTrials.gov, identifier: NCT00799890.
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http://dx.doi.org/10.3389/fneur.2021.615790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113620PMC
April 2021

Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration.

JAMA Neurol 2021 May 10. Epub 2021 May 10.

Department of Neurology, University of California, Irvine, Irvine.

Importance: N-glycan branching modulates cell surface receptor availability, and its deficiency in mice promotes inflammatory demyelination, reduced myelination, and neurodegeneration. N-acetylglucosamine (GlcNAc) is a rate-limiting substrate for N-glycan branching, but, to our knowledge, endogenous serum levels in patients with multiple sclerosis (MS) are unknown.

Objective: To investigate a marker of endogenous serum GlcNAc levels in patients with MS.

Design, Setting, And Participants: A cross-sectional discovery study and cross-sectional confirmatory study were conducted at 2 academic MS centers in the US and Germany. The discovery study recruited 54 patients with MS from an outpatient clinic as well as 66 healthy controls between April 20, 2010, and June 21, 2013. The confirmatory study recruited 180 patients with MS from screening visits at an academic MS study center between April 9, 2007, and February 29, 2016. Serum samples were analyzed from December 2, 2013, to March 2, 2015. Statistical analysis was performed from February 23, 2020, to March 18, 2021.

Main Outcomes And Measures: Serum levels of GlcNAc plus its stereoisomers, termed N-acetylhexosamine (HexNAc), were assessed using targeted tandem mass spectroscopy. Secondary outcomes (confirmatory study) comprised imaging and clinical disease markers.

Results: The discovery cohort included 66 healthy controls (38 women; mean [SD] age, 42 [20] years), 33 patients with relapsing-remitting MS (RRMS; 25 women; mean [SD] age, 50 [11] years), and 21 patients with progressive MS (PMS; 14 women; mean [SD] age, 55 [7] years). The confirmatory cohort included 125 patients with RRMS (83 women; mean [SD] age, 40 [9] years) and 55 patients with PMS (22 women; mean [SD] age, 49 [80] years). In the discovery cohort, the mean (SD) serum level of GlcNAc plus its stereoisomers (HexNAc) was 710 (174) nM in healthy controls and marginally reduced in patients with RRMS (mean [SD] level, 682 [173] nM; P = .04), whereas patients with PMS displayed markedly reduced levels compared with healthy controls (mean [SD] level, 548 [101] nM; P = 9.55 × 10-9) and patients with RRMS (P = 1.83 × 10-4). The difference between patients with RRMS (mean [SD] level, 709 [193] nM) and those with PMS (mean [SD] level, 405 [161] nM; P = 7.6 × 10-18) was confirmed in the independent confirmatory cohort. Lower HexNAc serum levels correlated with worse expanded disability status scale scores (ρ = -0.485; P = 4.73 × 10-12), lower thalamic volume (t = 1.7; P = .04), and thinner retinal nerve fiber layer (B = 0.012 [SE = 7.5 × 10-11]; P = .008). Low baseline serum HexNAc levels correlated with a greater percentage of brain volume loss at 18 months (t = 1.8; P = .04).

Conclusions And Relevance: This study suggests that deficiency of GlcNAc plus its stereoisomers (HexNAc) may be a biomarker for PMS. Previous preclinical, human genetic, and ex vivo human mechanistic studies revealed that N-glycan branching and/or GlcNAc may reduce proinflammatory responses, promote myelin repair, and decrease neurodegeneration. Combined, the data suggest that GlcNAc deficiency may be associated with progressive disease and neurodegeneration in patients with MS.
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http://dx.doi.org/10.1001/jamaneurol.2021.1116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111565PMC
May 2021

Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

J Neuroinflammation 2021 May 1;18(1):105. Epub 2021 May 1.

Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG) NMOSD.

Methods: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG patients over a median observation period of 4.25 years.

Results: In patients with AQP4-IgG NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG, but not MOG-IgG patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG, but not MOG-IgG patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG NMOSD. Patients with AQP4-IgG NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75 age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG NMOSD.

Conclusion: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG NMOSD in phases of clinical remission.
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http://dx.doi.org/10.1186/s12974-021-02138-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088712PMC
May 2021

The APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Neurology 2021 Apr 28. Epub 2021 Apr 28.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts, and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.

Results: One hundred sixteen authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point-checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans; we suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.

Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence class III, GRADE criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, fundoscopic imaging, post-acquisition data selection, post-acquisition analysis, nomenclature and abbreviations, and statistical approach. It will still be essential to update these recommendations to new research and practices regularly.
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http://dx.doi.org/10.1212/WNL.0000000000012125DOI Listing
April 2021

Longitudinal analysis of T1w/T2w ratio in patients with multiple sclerosis from first clinical presentation.

Mult Scler 2021 Apr 15:13524585211003479. Epub 2021 Apr 15.

Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany/ NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany/Einstein Center for Neurosciences, Berlin, Germany/Department of Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Background: Cross-sectional studies suggest normal appearing white matter (NAWM) integrity loss may lead to cortical atrophy in late-stage relapsing-remitting multiple sclerosis (MS).

Objective: To investigate the relationship between NAWM integrity and cortical thickness from first clinical presentation longitudinally.

Methods: NAWM integrity and cortical thickness were assessed with 3T magnetic resonance imaging (MRI) in 102 patients with clinically isolated syndrome or early MS (33.2 (20.1-60.1) years old, 68% female) from first clinical presentation over 2.8 ± 1.6 years. Fifty healthy controls (HCs) matched for age and sex were included. NAWM integrity was evaluated using the standardized T1w/T2w ratio (sT1w/T2w). The association between sT1w/T2w and cortical thickness was assessed using linear mixed models. The effect of disease activity was investigated using the No Evidence of Disease Activity (NEDA-3) criteria.

Results: At baseline, sT1w/T2w ( = 0.152) and cortical thickness ( = 0.489) did not differ from HCs. Longitudinally, decreasing sT1w/T2w was associated with cortical thickness and increasing lesion burden (marginal  = 0.061). The association was modulated by failing NEDA-3 (marginal  = 0.097).

Conclusion: sT1w/T2w may be a useful MRI biomarker for early MS, detecting relevant NAWM damage over time using conventional MRI scans, although with less sensitivity compared to quantitative measures.
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http://dx.doi.org/10.1177/13524585211003479DOI Listing
April 2021

A novel investigation method for axonal damage in neuromyelitis optica spectrum disorder: In vivo corneal confocal microscopy.

Mult Scler J Exp Transl Clin 2021 Jan-Mar;7(1):2055217321998060. Epub 2021 Mar 19.

Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disorder that damages optic nerves, brainstem, and spinal cord. In vivo corneal confocal microscopy (IVCM) is a noninvasive technique that provides corneal images with dendritic cells (DCs) and corneal subbasal nerve plexus (SBP), which arises from the trigeminal nerve.

Objective: We investigated corneal SBP changes in NMOSD and proposed IVCM as a potential new disease severity biomarker for NMOSD.

Methods: Seventeen age-sex matched NMOSD patients and 19 healthy participants underwent complete neurologic and ophthalmologic examinations. The duration of disease, first symptom, presence of optic neuritis attack, antibody status, Expanded Disability Status Scale(EDSS) score and disease severity score(DSS) were recorded. Retinal nerve fibre layer (RNFL) thickness was measured with optical coherence tomography, and corneal SBP images were taken with IVCM.

Results: NMOSD patients had significantly reduced corneal nerve fibre lenght-density and corneal nerve branch lenght-density compared with controls, while DC density was increased. NMOSD patients also showed significantly reduced RNFL thickness compared with controls. EDSS,DSS levels were inversely correlated with IVCM parameters.

Conclusion: We observed significant corneal nerve fibre loss in NMOSD patients in relation to disease severity. IVCM can be a candidate noninvasive imaging method for axonal damage assessment in NMOSD that warrants further investigation.
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http://dx.doi.org/10.1177/2055217321998060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985945PMC
March 2021

Cultural bias in motor function patterns: Potential relevance for predictive, preventive, and personalized medicine.

EPMA J 2021 Mar 3;12(1):91-101. Epub 2021 Mar 3.

Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 113125 Berlin, Germany.

Background: Quantification of motor performance has a promising role in personalized medicine by diagnosing and monitoring, e.g. neurodegenerative diseases or health problems related to aging. New motion assessment technologies can evolve into patient-centered eHealth applications on a global scale to support personalized healthcare as well as treatment of disease. However, uncertainty remains on the limits of generalizability of such data, which is relevant specifically for preventive or predictive applications, using normative datasets to screen for incipient disease manifestations or indicators of individual risks.

Objective: This study explored differences between healthy German and Japanese adults in the performance of a short set of six motor tests.

Methods: Six motor tasks related to gait and balance were recorded with a validated 3D camera system. Twenty-five healthy adults from Chiba, Japan, participated in this study and were matched for age, sex, and BMI to a sample of 25 healthy adults from Berlin, Germany. Recordings used the same technical setup and standard instructions and were supervised by the same experienced operator. Differences in motor performance were analyzed using multiple linear regressions models, adjusted for differences in body stature.

Results: From 23 presented parameters, five showed group-related differences after adjustment for height and weight ( between .19 and .46, p<.05). Japanese adults transitioned faster between sitting and standing and used a smaller range of hand motion. In stepping-in-place, cadence was similar in both groups, but Japanese adults showed higher knee movement amplitudes. Body height was identified as relevant confounder (standardized beta >.5) for performance of short comfortable and maximum speed walks. For results of posturography, regression models did not reveal effects of group or body stature.

Conclusions: Our results support the existence of a population-specific bias in motor function patterns in young healthy adults. This needs to be considered when motor function is assessed and used for clinical decisions, especially for personalized predictive and preventive medical purposes. The bias affected only the performance of specific items and parameters and is not fully explained by population-specific ethnic differences in body stature. It may be partially explained as cultural bias related to motor habits. Observed effects were small but are expected to be larger in a non-controlled cross-cultural application of motion assessment technologies with relevance for related algorithms that are being developed and used for data processing. In sum, the interpretation of individual data should be related to appropriate population-specific or even better personalized normative values to yield its full potential and avoid misinterpretation.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-021-00236-3.
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http://dx.doi.org/10.1007/s13167-021-00236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954970PMC
March 2021

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder.

Ann Clin Transl Neurol 2021 04 19;8(4):774-789. Epub 2021 Mar 19.

Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany.

Objectives: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging.

Methods: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS).

Results: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls.

Interpretation: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG.
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http://dx.doi.org/10.1002/acn3.51315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045942PMC
April 2021

Lateral geniculate nucleus volume changes after optic neuritis in neuromyelitis optica: A longitudinal study.

Neuroimage Clin 2021 4;30:102608. Epub 2021 Mar 4.

Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Neurology, University of California Irvine, CA, USA. Electronic address:

Objectives: Lateral geniculate nucleus (LGN) volume is reduced after optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD). We aimed at a longitudinal assessment of LGN volume in NMOSD.

Methods: Twenty-nine patients with aquaporin 4-IgG seropositive NMOSD (age: 47.8 ± 14.6 years (y), female: n = 27, history of ON (NMO-ON): n = 17, median time since ON: 3[1.2-12.1]y) and 18 healthy controls (HC; age: 39.3 ± 15.8y; female: n = 13) were included. Median follow-up was 4.1[1.1-4.7]y for patients and 1.7[0.9-3.2]y for HC. LGN volume was measured using a multi-atlas-based approach of automated segmentation on 3 Tesla magnetic resonance images. Retinal optical coherence tomography and probabilistic tractography of the optic radiations (OR) were also performed.

Results: At baseline, NMO-ON patients had lower LGN volumes (395.4 ± 48.9 mm) than patients without ON (NMO-NON: 450.7 ± 55.6 mm; p = 0.049) and HC (444.5 ± 61.5 mm, p = 0.025). LGN volume was associated with retinal neuroaxonal loss and microstructural OR damage. Longitudinally, there was no change in LGN volumes in the absence of ON, neither in all patients (B = -0.6, SE = 1.4, p = 0.670), nor in NMO-ON (B = -0.8, SE = 1.6, p = 0.617) and NMO-NON (B = 1.7, SE = 3.5, p = 0.650). However, in four patients with new ON during follow-up, LGN volume was reduced at last visit (median time since ON: 2.6 [1.8-3.9]y) compared to the measurement before ON (352 ± 52.7 vs. 371.1 ± 55.9 mm; t = -3.6, p = 0.036).

Conclusion: Although LGN volume is reduced after ON in NMOSD, this volume loss is not progressive over longer follow-up or independent of ON. Thus, our findings -at least in this relatively small cohort- do not support occult neurodegeneration of the afferent visual pathway in NMOSD.
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http://dx.doi.org/10.1016/j.nicl.2021.102608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974320PMC
March 2021

Epigallocatechin Gallate in Progressive MS: A Randomized, Placebo-Controlled Trial.

Neurol Neuroimmunol Neuroinflamm 2021 05 23;8(3). Epub 2021 Feb 23.

From the Charité - Universitätsmedizin Berlin (R.R., C.C., M.S., A.U.B., J.D., K.K., H.Z., M.L., K.-D.W., J.B.-S., F.P.), Berlin, Germany; and Jens Würfel, University Basel, Basel, Switzerland.

Objective: To examine whether treatment with epigallocatechin gallate (EGCG) influences progression of brain atrophy, reduces clinical and further radiologic disease activity markers, and is safe in patients with progressive multiple sclerosis (PMS).

Methods: We enrolled 61 patients with primary or secondary PMS in a randomized double-blind, parallel-group, phase II trial on oral EGCG (up to 1,200 mg daily) or placebo for 36 months with an optional open-label EGCG treatment extension (OE) of 12-month duration. The primary end point was the rate of brain atrophy, quantified as brain parenchymal fraction (BPF). The secondary end points were radiologic and clinical disease parameters and safety assessments.

Results: In our cohort, 30 patients were randomized to EGCG treatment and 31 to placebo. Thirty-eight patients (19 from each group) completed the study. The primary endpoint was not met, as in 36 months the rate of decrease in BPF was 0.0092 ± 0.0152 in the treatment group and -0.0078 ± 0.0159 in placebo-treated patients. None of the secondary MRI and clinical end points revealed group differences. Adverse events of EGCG were mostly mild and occurred with a similar incidence in the placebo group. One patient in the EGCG group had to stop treatment due to elevated aminotransferases (>3.5 times above normal limit).

Conclusions: In a phase II trial including patients with multiple sclerosis (MS) with progressive disease course, we were unable to demonstrate a treatment effect of EGCG on the primary and secondary radiologic and clinical disease parameters while confirming on overall beneficial safety profile.

Clinicaltrialgov Identifier: NCT00799890.

Classification Of Evidence: This phase II trial provides Class II evidence that for patients with PMS, EGCG was safe, well tolerated, and did not significantly reduce the rate of brain atrophy.
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http://dx.doi.org/10.1212/NXI.0000000000000964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954462PMC
May 2021

N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation.

J Biol Chem 2020 12;295(51):17413-17424

Department of Neurology, University of California Irvine, Irvine, California, USA; Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, California, USA. Electronic address:

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.
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http://dx.doi.org/10.1074/jbc.RA120.015595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762951PMC
December 2020

Transdiagnostic hippocampal damage patterns in neuroimmunological disorders.

Neuroimage Clin 2020 27;28:102515. Epub 2020 Nov 27.

Charité - Universitätsmedizin Berlin, Department of Neurology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin Center for Advanced Neuroimaging, Berlin, Germany; Humboldt-Universität zu Berlin, Berlin School of Mind and Brain, Berlin, Germany. Electronic address:

Hippocampal damage and associated cognitive deficits are frequently observed in neuroimmunological disorders, but comparative analyses to identify shared hippocampal damage patterns are missing. Here, we adopted a transdiagnostic analytical approach and investigated hippocampal shape deformations and associated cognitive deficits in four neuroimmunological diseases. We studied 120 patients (n = 30 in each group), including patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), anti-NMDAR and anti-LGI1 encephalitis. A control group was matched to each patient sample from a pool of 79 healthy participants. We performed an MRI-based vertex-wise hippocampal shape analysis, extracted hippocampal volume estimates and scalar projection values as a measure of surface displacement. Cognitive testing included assessment of verbal memory and semantic fluency performance. Our cross-sectional analyses revealed characteristic patterns of bilateral inward deformations covering up to 32% of the hippocampal surface in MS, anti-NMDAR encephalitis, and anti-LGI1 encephalitis, whereas NMOSD patients showed no deformations compared to controls. Significant inversions were noted mainly on the hippocampal head, were accompanied by volume loss, and correlated with semantic fluency scores and verbal episodic memory in autoimmune encephalitis and MS. A deformation overlap analysis across disorders revealed a convergence zone on the left anterior hippocampus that corresponds to the CA1 subfield. This convergence zone indicates a shared downstream substrate of immune-mediated damage that appears to be particularly vulnerable to neuroinflammatory processes. Our transdiagnostic morphological view sheds light on mutual pathophysiologic pathways of cognitive deficits in neuroimmunological diseases and stimulates further research into the mechanisms of increased susceptibility of the hippocampus to autoimmunity.
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http://dx.doi.org/10.1016/j.nicl.2020.102515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721635PMC
November 2020

Quantitative Multi-Parameter Mapping Optimized for the Clinical Routine.

Front Neurosci 2020 7;14:611194. Epub 2020 Dec 7.

Berlin Center for Advanced Neuroimaging, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health Berlin, Berlin, Germany.

Using quantitative multi-parameter mapping (MPM), studies can investigate clinically relevant microstructural changes with high reliability over time and across subjects and sites. However, long acquisition times (20 min for the standard 1-mm isotropic protocol) limit its translational potential. This study aimed to evaluate the sensitivity gain of a fast 1.6-mm isotropic MPM protocol including post-processing optimized for longitudinal clinical studies. 6 healthy volunteers (35±7 years old; 3 female) were scanned at 3T to acquire the following whole-brain MPM maps with 1.6 mm isotropic resolution: proton density (PD), magnetization transfer saturation (MT), longitudinal relaxation rate (R1), and transverse relaxation rate (R2). MPM maps were generated using two RF transmit field (B1+) correction methods: (1) using an acquired B1+ map and (2) using a data-driven approach. Maps were generated with and without Gibb's ringing correction. The intra-/inter-subject coefficient of variation (CoV) of all maps in the gray and white matter, as well as in all anatomical regions of a fine-grained brain atlas, were compared between the different post-processing methods using Student's -test. The intra-subject stability of the 1.6-mm MPM protocol is 2-3 times higher than for the standard 1-mm sequence and can be achieved in less than half the scan duration. Intra-subject variability for all four maps in white matter ranged from 1.2-5.3% and in gray matter from 1.8 to 9.2%. Bias-field correction using an acquired B1+ map significantly improved intra-subject variability of PD and R1 in the gray (42%) and white matter (54%) and correcting the raw images for the effect of Gibb's ringing further improved intra-subject variability in all maps in the gray (11%) and white matter (10%). Combining Gibb's ringing correction and bias field correction using acquired B1+ maps provides excellent stability of the 7-min MPM sequence with 1.6 mm resolution suitable for the clinical routine.
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http://dx.doi.org/10.3389/fnins.2020.611194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750476PMC
December 2020

Blunted neural and psychological stress processing predicts future grey matter atrophy in multiple sclerosis.

Neurobiol Stress 2020 Nov 27;13:100244. Epub 2020 Jul 27.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, And Berlin Institute of Health, NeuroCure Clinical Research Center, 10117, Berlin, Germany.

Background: Multiple sclerosis (MS) is characterized by two neuropathological key aspects: inflammation and neurodegeneration. Clinical studies support a prospective link between psychological stress and subsequent inflammatory disease activity. However, it is unknown if a similar link exists for grey matter (GM) degeneration as the key driver of irreversible disability.

Methods: We tested whether neural network activity triggered in a psychological fMRI stress paradigm (a mental arithmetic task including social evaluation) conducted at a baseline time point predicts future GM atrophy in 25 persons with MS (14 females). Atrophy was determined between the baseline and a follow-up time point with a median delay of 1012 (Rg: 717-1439) days. Additionally, atrophy was assessed in 22 healthy subjects (13 females; median delay 771 [Rg: 740-908] days between baseline and follow-up) for comparison.

Results: An analysis of longitudinal atrophy in patients revealed GM loss in frontal, parietal, and cerebellar areas. Cerebellar atrophy was more pronounced in patients than controls. Future parietal and cerebellar atrophy could be predicted based on activity of two networks. Perceived psychological stress was negatively related to future parietal atrophy in patients and activity of the network predictive of parietal atrophy was positively linked to perceived stress.

Conclusions: We have shown that blunted neural and psychological stress processing have a detrimental effect on the course of MS and are interrelated. Together with research showing that psychological and neural stress processing can be altered through interventions, our findings suggest that stress processing might constitute an important modifiable disease factor.
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http://dx.doi.org/10.1016/j.ynstr.2020.100244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739031PMC
November 2020

Ventral posterior nucleus volume is associated with neuropathic pain intensity in neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2020 Nov 13;46:102579. Epub 2020 Oct 13.

Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Neurology, University of California Irvine, CA, USA.

Background: Neuropathic pain (NP) is frequent in neuromyelitis optica spectrum disorders (NMOSD). The ventral posterior nucleus (VPN) of the thalamus receives sensory afferences from the spinothalamic tracts and is associated with central pain in other conditions.

Objective: To investigate associations between NP and VPN volume in aquaporin-4-IgG- positive (AQP4-IgG+) NMOSD.

Methods: This cross-sectional study included 32 AQP4-IgG+ NMOSD patients and 37 healthy controls. NP intensity was determined by the PainDetect Questionnaire. Spinal cord lesion number and location as well as VPN volume were assessed by MRI, the latter using a multi-atlas-based automated segmentation.

Results: Twenty-five patients (78%) suffered from NP and seven had no pain. Mean VPN volume did not differ between patients with and without NP (p=0.533) or between patients and controls. However, mean VPN volume correlated with average (rho=-0.486, p=0.019) and worst pain intensity (rho=-0.593, p=0.003). Of note, no other thalamic nuclei volumes correlated with measures of pain intensity. Compared to pain-free patients, patients with NP had more lesions involving the thoracic spinal cord (p=0.007). The relationships between VPN and pain intensity measures remained after adjustment for age, myelitis count, and spinal cord lesion location.

Conclusion: Our data support a model where thoracic spinal cord lesions are associated with the development of NP in AQP4-IgG+ NMOSD and the VPN plays a role in the modulation of NP intensity. VPN volume as assessed in our study may be a clinically meaningful imaging marker of pain severity in AQP4-IgG+ NMOSD.
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http://dx.doi.org/10.1016/j.msard.2020.102579DOI Listing
November 2020

Magnetic resonance T1w/T2w ratio in the middle cerebellar peduncle might be a sensitive biomarker for multiple system atrophy.

Eur Radiol 2021 Jun 25;31(6):4277-4284. Epub 2020 Nov 25.

Department of Neurology, Graduate School of Medicine, Chiba University 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan.

Objective: We aimed to investigate the use of a myelin-sensitive MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, for detecting early changes in the middle cerebellar peduncle (MCP) in cerebellar subtype multiple system atrophy (MSA-C) patients.

Methods: We included 28 MSA-C patients, including a subset of 17 MSA-C patients within 2 years of disease onset (early MSA-C), and 28 matched healthy controls. T1w and T2w scans were acquired using a 3-T MR system. The sT1w/T2w ratio in MCP was analyzed using SPM12 by utilizing a region-of-interest approach in normalized space. The diagnostic performance of the MCP sT1w/T2w ratio in discriminating MSA-C and the subgroup of early MSA-C from the matched controls was assessed. Correlation analyses were performed to evaluate the relationship between the MCP sT1w/T2w ratio and other clinical parameters including the International Cooperative Ataxia Scale (ICARS) score for quantifying cerebellar ataxia.

Results: Compared to controls, the sT1w/T2w ratio in the MCP was markedly lower in all (p < 0.001) MSA-C patients and 17 early (p < 0.001) MSA-C patients. The MCP sT1w/T2w ratio had high sensitivity (96%) and specificity (100%) to distinguish MSA-C from controls (area under the curve = 0.99), even for the early MSA-C group (area under the curve = 0.99; sensitivity = 94%, specificity = 100%). The MCP sT1w/T2w ratio correlated with the ICARS score in early MSA-C.

Conclusions: The sT1w/T2w ratio can detect MSA-C-related changes in the MCP, even in the early stages of the disorder, and could be a sensitive biomarker for MSA-C.

Key Points: • The sT1w/T2w ratio can detect MSA-C-related changes in the middle cerebellar peduncle, even in the early stages of the disorder. • The middle cerebellar peduncle sT1w/T2w ratio correlated with a cerebellar ataxia score in early MSA-C patients.
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http://dx.doi.org/10.1007/s00330-020-07521-1DOI Listing
June 2021

Longitudinal analysis of primary and secondary factors related to fatigue in multiple sclerosis.

Acta Neurol Belg 2021 Feb 13;121(1):271-274. Epub 2020 Nov 13.

Experimental and Clinical Research Center, Max-Delbrück-Centrum für Molekulare Medizin and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany.

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http://dx.doi.org/10.1007/s13760-020-01545-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937598PMC
February 2021

Cohort profile: a collaborative multicentre study of retinal optical coherence tomography in 539 patients with neuromyelitis optica spectrum disorders (CROCTINO).

BMJ Open 2020 10 29;10(10):e035397. Epub 2020 Oct 29.

Neurological Department and Institute of Experimental Neurology (INSPE) Scientific Institute, Hospital San Raffaele; and University Vita-Salute San Raffaele, Milan, Italy.

Purpose: Optical coherence tomography (OCT) captures retinal damage in neuromyelitis optica spectrum disorders (NMOSD). Previous studies investigating OCT in NMOSD have been limited by the rareness and heterogeneity of the disease. The goal of this study was to establish an image repository platform, which will facilitate neuroimaging studies in NMOSD. Here we summarise the profile of the Collaborative OCT in NMOSD repository as the initial effort in establishing this platform. This repository should prove invaluable for studies using OCT to investigate NMOSD.

Participants: The current cohort includes data from 539 patients with NMOSD and 114 healthy controls. These were collected at 22 participating centres from North and South America, Asia and Europe. The dataset consists of demographic details, diagnosis, antibody status, clinical disability, visual function, history of optic neuritis and other NMOSD defining attacks, and OCT source data from three different OCT devices.

Findings To Date: The cohort informs similar demographic and clinical characteristics as those of previously published NMOSD cohorts. The image repository platform and centre network continue to be available for future prospective neuroimaging studies in NMOSD. For the conduct of the study, we have refined OCT image quality criteria and developed a cross-device intraretinal segmentation pipeline.

Future Plans: We are pursuing several scientific projects based on the repository, such as analysing retinal layer thickness measurements, in this cohort in an attempt to identify differences between distinct disease phenotypes, demographics and ethnicities. The dataset will be available for further projects to interested, qualified parties, such as those using specialised image analysis or artificial intelligence applications.
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http://dx.doi.org/10.1136/bmjopen-2019-035397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597491PMC
October 2020

Altered Coupling of Psychological Relaxation and Regional Volume of Brain Reward Areas in Multiple Sclerosis.

Front Neurol 2020 6;11:568850. Epub 2020 Oct 6.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, NeuroCure Clinical Research Center, Berlin, Germany.

Psychological stress can influence the severity of multiple sclerosis (MS), but little is known about neurobiological factors potentially counteracting these effects. To identify gray matter (GM) brain regions related to relaxation after stress exposure in persons with MS (PwMS). 36 PwMS and 21 healthy controls (HCs) reported their feeling of relaxation during a mild stress task. These markers were related to regional GM volumes, heart rate, and depressive symptoms. Relaxation was differentially linked to heart rate in both groups ( = 2.20, = 0.017), i.e., both markers were only related in HCs. Relaxation was positively linked to depressive symptoms across all participants ( = 1.99, = 0.045) although this link differed weakly between groups ( = 1.62, = 0.108). Primarily, the volume in medial temporal gyrus was negatively linked to relaxation in PwMS ( = -5.55, p = 0.018). A group-specific coupling of relaxation and GM volume was found in ventromedial prefrontal cortex (VMPFC) ( = -4.89, p = 0.039). PwMS appear unable to integrate peripheral stress signals into their perception of relaxation. Together with the group-specific coupling of relaxation and VMPFC volume, a key area of the brain reward system for valuation of affectively relevant stimuli, this finding suggests a clinically relevant misinterpretation of stress-related affective stimuli in MS.
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http://dx.doi.org/10.3389/fneur.2020.568850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574404PMC
October 2020

Differences in Advanced Magnetic Resonance Imaging in MOG-IgG and AQP4-IgG Seropositive Neuromyelitis Optica Spectrum Disorders: A Comparative Study.

Front Neurol 2020 30;11:499910. Epub 2020 Sep 30.

NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

To explore differences in advanced brain magnetic resonance imaging (MRI) characteristics between myelin oligodendrocyte (MOG) immunoglobulin (IgG) and aquaporin-4 (AQP4) IgG seropositive (+) neuromyelitis optica spectrum disorders (NMOSD). 33 AQP4-IgG and 18 MOG-IgG seropositive NMOSD patients and 61 healthy control (HC) subjects were included. All 112 participants were scanned with the same standardized MRI-protocol on a 3-Tesla MRI-scanner. Brain volume and diffusion tensor imaging (DTI) parameters were assessed. MOG-IgG+ patients showed reduced parallel diffusivity within white matter tracts compared to HC whereas AQP4-IgG+ showed no significant brain parenchymal damage in DTI analysis. AQP4-IgG+ patients showed reduced whole brain volumes and reduced volumes of several deep gray matter structures compared to HC whereas MOG-IgG+ patients did not show reduced brain or deep gray matter volumes compared to HC. Microstructural brain parenchymal damage in MOG-IgG+ patients was more pronounced than in AQP4-IgG+ patients, compared with HC, whereas normalized brain volume reduction was more severe in AQP4-IgG+ patients. Longitudinal imaging studies are warranted to further investigate this trend in NMOSD. Our results suggest that MOG-IgG+ and AQP4-IgG+ NMOSD patients differ in cerebral MRI characteristics. Advanced MRI analysis did not help to differentiate between MOG-IgG+ and AQP4-IgG+ patients in our study.
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http://dx.doi.org/10.3389/fneur.2020.499910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554609PMC
September 2020

Neurochemical Differences in Spinocerebellar Ataxia Type 14 and 1.

Cerebellum 2021 Apr 15;20(2):169-178. Epub 2020 Oct 15.

Department of Neurology, Charité University Medicine Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Autosomal-dominant spinocerebellar ataxias (SCA) are neurodegenerative diseases characterized by progressive ataxia. Here, we report on neurometabolic alterations in spinocerebellar ataxia type 1 (SCA1; SCA-ATXN1) and 14 (SCA14; SCA-PRKCG) assessed by non-invasive H magnetic resonance spectroscopy. Three Tesla H magnetic resonance spectroscopy was performed in 17 SCA14, 14 SCA1 patients, and in 31 healthy volunteers. We assessed metabolites in the cerebellar vermis, right cerebellar hemisphere, pons, prefrontal, and motor cortex. Additionally, clinical characteristics were obtained for each patient to correlate them with metabolites. In SCA14, metabolic changes were restricted to the cerebellar vermis compared with widespread neurochemical alterations in SCA1. In SCA14, total N-acetylaspartate (tNAA) was reduced in the vermis by 34%. In SCA1, tNAA was reduced in the vermis (24%), cerebellar hemisphere (26%), and pons (25%). SCA14 patients showed 24% lower glutamate+glutamine (Glx) and 46% lower γ-aminobutyric acid (GABA) in the vermis, while SCA1 patients showed no alterations in Glx and GABA. SCA1 revealed a decrease of aspartate (Asp) in the vermis (62%) and an elevation in the prefrontal cortex (130%) as well as an elevation of myo-inositol (Ins) in the cerebellar hemisphere (51%) and pons (46%). No changes of Asp and Ins were detected in SCA14. Beyond, glucose (Glc) was increased in the vermis of both SCA14 (155%) and SCA1 (247%). H magnetic resonance spectroscopy revealed differing neurochemical profiles in SCA1 and SCA14 and confirmed metabolic changes that may be indicative for neuronal loss and dysfunctional energy metabolism. Therefore, H magnetic resonance spectroscopy represents a helpful tool for in-vivo tracking of disease-specific pathophysiology.
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http://dx.doi.org/10.1007/s12311-020-01201-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004522PMC
April 2021

Imaging markers of disability in aquaporin-4 immunoglobulin G seropositive neuromyelitis optica: a graph theory study.

Brain Commun 2019 16;1(1):fcz026. Epub 2019 Oct 16.

Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité -Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.

Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16 ± 14.3 years, female:male = 36:4) and 31 healthy controls (age = 45.92 ± 13.3 years, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens ( = -0.85,  = 0.021) and caudate nucleus ( = -0.61,  = 0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures.
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http://dx.doi.org/10.1093/braincomms/fcz026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425339PMC
October 2019

Sex differences in brain atrophy in multiple sclerosis.

Biol Sex Differ 2020 08 28;11(1):49. Epub 2020 Aug 28.

Department of Neurology, University of California, Los Angeles, 635 Charles E. Young Drive South, Gordon Neuroscience Research Building, Los Angeles, CA, 90095, USA.

Background: Women are more susceptible to multiple sclerosis (MS) than men by a ratio of approximately 3:1. However, being male is a risk factor for worse disability progression. Inflammatory genes have been linked to susceptibility, while neurodegeneration underlies disability progression. Thus, there appears to be a differential effect of sex on inflammation versus neurodegeneration. Further, gray matter (GM) atrophy is not uniform across the brain in MS, but instead shows regional variation. Here, we study sex differences in neurodegeneration by comparing regional GM atrophy in a cohort of men and women with MS versus their respective age- and sex-matched healthy controls.

Methods: Voxel-based morphometry (VBM), deep GM substructure volumetry, and cortical thinning were used to examine regional GM atrophy.

Results: VBM analysis showed deep GM atrophy in the thalamic area in both men and women with MS, whereas men had additional atrophy in the putamen as well as in localized cortical regions. Volumetry confirmed deep GM loss, while localized cortical thinning confirmed GM loss in the cerebral cortex. Further, MS males exhibited worse performance on the 9-hole peg test (9HPT) than MS females. We observed a strong correlation between thalamic volume and 9HPT performance in MS males, but not in MS females.

Conclusion: More regional GM atrophy was observed in men with MS than women with MS, consistent with previous observations that male sex is a risk factor for worse disease progression.
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http://dx.doi.org/10.1186/s13293-020-00326-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456053PMC
August 2020

Optic Nerve Head Volumetry by Optical Coherence Tomography in Papilledema Related to Idiopathic Intracranial Hypertension.

Transl Vis Sci Technol 2020 02 21;9(3):24. Epub 2020 Feb 21.

Department of Neuroophthalmology, Eye Center, Medical Center, Medical Faculty, University of Freiburg, Germany.

Purpose: Idiopathic intracranial hypertension (IIH) leads to optic nerve head swelling and optic atrophy if left untreated. We wanted to assess an easy to perform volumetric algorithm to detect and quantify papilledema in comparison to retinal nerve fiber layer (RNFL) analysis using optical coherence tomography (OCT).

Methods: Participants with and without IIH underwent visual acuity testing at different contrast levels and static perimetry. Spectralis-OCT measurements comprised standard imaging of the peripapillary RNFL and macular ganglion cell layer (GCL). The optic nerve head volume (ONHV) was determined using the standard segmentation software and the 3.45 mm early treatment diabetic retinopathy study (ETDRS) grid, necessitating manual correction within Bruch membrane opening. Three neuro-ophthalmologists graded fundus images according to the Frisén scale. A mixed linear model (MLM) was used to determine differences between study groups. Sensitivity and specificity was evaluated using the area under the receiver-operating characteristic (ROC).

Results: Twenty-one patients with IIH had an increased ONHV of 6.46 ± 2.36 mm as compared to 25 controls with 3.20 ± 0.25 mm ( < 0.001). The ONHV cutoff distinguishing IIH from controls was 3.97 mm (i.e. no patient with IIH had an ONHV below and no healthy individual above this value). The area under the curve (AUC) for ONHV was 0.99 and for the RNFL at 3.5 mm 0.90. The Frisén scale grading correlated higher with the ONHV (r = 0.90) than with the RNFL thickness (r = 0.68). ONHV measurements were highly reproducible in both groups (coefficient of variation <0.01%).

Conclusions: OCT-based volumetry of the optic nerve head discriminates very accurately between individuals with and without IIH. It may serve as a useful adjunct to the rating with the subjective and ordinal Frisén scale.

Translational Relevance: A simple OCT protocol run on the proprietary software of a commercial OCT device can reliably discriminate between normal optic nerve heads or pseudo-papilledema and true papilledema while being highly reproducible. Our normative data and OCT preset may be used in further clinical studies.
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http://dx.doi.org/10.1167/tvst.9.3.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354856PMC
February 2020

Visual system damage and network maladaptation are associated with cognitive performance in neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2020 Oct 17;45:102406. Epub 2020 Jul 17.

NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine & Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Department of Neurology, University of California, Irvine, CA, USA. Electronic address:

Background Neuromyelitis Optica Spectrum Disorders (NMOSD) is an autoimmune disease leading to disability from optic neuritis, myelitis and more rarely brain stem attacks and encephalitis. Patients with NMOSD also exhibit cognitive deficits, the cause of which remains unclear. Recent evidence highlights sensory-cognitive parallel processing converging on the primary visual cortex. The objective of this study was to investigate the effect of the primary visual network disruption from damage caused by optic neuritis on cognition in NMOSD. Methods Twenty-nine aquaporin-4 antibody seropositive patients with NMOSD and 22 healthy controls (HC) completed the brief repeatable battery of neuropsychological tests (BRB-N) and underwent 3 Tesla MRI. Primary visual network functional connectivity (FC) at resting state was analyzed and correlated with performance on BRB-N. These correlations were compared between the groups. Results Patients performed significantly worse than HC on the BRB-N Index score (t = 2.366, p = 0.02). Among HC, visual network FC decreased significantly as cognitive performance on the BRB-N Index score increased (rho(17)=-0.507, p = 0.02). Among patients, this association was absent (rho(23)=0.197, p = 0.18), and the difference in correlation direction and strength to HC was significant (z=-2.175, p = 0.01). Visual network FC was able to explain 19% of the variance in cognitive performance in HC, but none in patients. Conclusions A physiological association of the primary visual network FC and cognitive performance appears absent in patients with NMOSD, suggesting a partial explanation for cognitive deficits. Our findings extend neuroscientific concepts on sensory-cognitive parallel processing neural networks to a clearly defined pathological state, and may be relevant for other diseases with visual system damage.
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http://dx.doi.org/10.1016/j.msard.2020.102406DOI Listing
October 2020

Functionally Relevant Maculopathy and Optic Atrophy in Spinocerebellar Ataxia Type 1.

Mov Disord Clin Pract 2020 Jul 6;7(5):502-508. Epub 2020 May 6.

Experimental and Clinical Research Center, Max-Delbrück-Centrum für Molekulare Medizin and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin Humboldt-Universität zu Berlin, and Berlin Institute of Health Berlin Germany.

Background: Spinocerebellar ataxia type 1 (SCA-ATXN1) is an inherited progressive ataxia disorder characterized by an adult-onset cerebellar syndrome combined with nonataxia signs. Retinal or optic nerve affection are not systematically described.

Objectives: To describe a retinal phenotype and its functional relevance in SCA-ATXN1.

Methods: We applied optical coherence tomography (OCT) in 20 index cases with SCA-ATXN1 and 22 healthy controls (HCs), investigating qualitative changes and quantifying the peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIP) volume as markers of optic atrophy and outer retinal layers as markers of maculopathy. Visual function was assessed by high- (HC-VA) and low-contrast visual acuity (LC-VA) and the Hardy-Rand-Rittler pseudoisochromatic test for color vision.

Results: Five patients (25%) showed distinct maculopathies in the ellipsoid zone (EZ). Furthermore, pRNFL ( < 0.001) and GCIP ( = 0.002) were reduced in patients (pRNFL, 80.86 ± 9.49 μm; GCIP, 1.84 ± 0.16 mm) compared with HCs (pRNFL, 97.02 ± 8.34 μm; GCIP, 1.98 ± 0.12 mm). Outer macular layers were similar between groups, but reduced in patients with maculopathies. HC-VA ( = 0.002) and LC-VA ( < 0.001) were reduced in patients (HC-VA [logMAR]: 0.01 ± 010; LC-VA [logMAR]: 0.44 ± 0.16) compared with HCs (HC-VA [logMAR]: -0.12 ± 0.08; LC-VA [logMAR]: 0.25 ± 0.05). Color vision was abnormal in 2 patients with maculopathies.

Conclusions: A distinct maculopathy, termed EZ disruption, as well as optic atrophy add to the known nonataxia features in SCA-ATXN1. Whereas optic atrophy may be understood as part of a widespread neurodegeneration, EZ disruption may be explained by effects of ataxin-1 gene or protein on photoreceptors. Our findings extend the spectrum of nonataxia signs in SCA-ATXN1 with potential relevance for diagnosis and monitoring.
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http://dx.doi.org/10.1002/mdc3.12949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328427PMC
July 2020

Altered fovea in AQP4-IgG-seropositive neuromyelitis optica spectrum disorders.

Neurol Neuroimmunol Neuroinflamm 2020 09 23;7(5). Epub 2020 Jun 23.

From the Experimental and Clinical Research Center (S.M., F.C.O., J.B.-S., H.G.Z., F.P., A.U.B.), Max-Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; NeuroCure Clinical Research Center (S.M., F.C.O., S.K.Y., E.M.K., J.B.-S., H.G.Z., F.P., A.U.B.), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Division of Neuroinflammation and Glial Biology (F.C.O.), University of California, San Francisco; Nocturne GmbH (S.K.Y., E.M.K.), Berlin; Department of Neurology (M.W., M.R., O.A., P.A.), Medical Faculty, Heinrich Heine University, Düsseldorf; Institute of Clinical Neuroimmunology (J.H.), LMU Hospital, Ludwig-Maximilians University, Munich; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf; Department of Neurology (K.R., F.P.), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; and Department of Neurology (A.U.B.), University of California, Irvine.

Objective: To investigate disease-specific foveal shape changes in patients with neuromyelitis optica spectrum disorders (NMOSDs) using foveal morphometry.

Methods: This cross-sectional study included macular spectral domain optical coherence tomography scans of 52 eyes from 28 patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD, 116 eyes from 60 patients with MS, and 123 eyes from 62 healthy controls (HCs), retrospectively, and an independent confirmatory cohort comprised 33/33 patients with NMOSD/MS. The fovea was characterized using 3D foveal morphometry. We included peripapillary retinal nerve fiber layer (pRNFL) thickness and combined macular ganglion cell and inner plexiform layer (GCIPL) volume to account for optic neuritis (ON)-related neuroaxonal damage.

Results: Group comparison showed significant differences compared with HC in the majority of foveal shape parameters in NMOSD, but not MS. Pit flat disk area, average pit flat disk diameter, inner rim volume, and major slope disk length, as selected parameters, showed differences between NMOSD and MS ( value = 0.017, 0.002, 0.005, and 0.033, respectively). This effect was independent of ON. Area under the curve was between 0.7 and 0.8 (receiver operating characteristic curve) for discriminating between NMOSD and MS. Pit flat disk area and average pit flat disk diameter changes independent of ON were confirmed in an independent cohort.

Conclusions: Foveal morphometry reveals a wider and flatter fovea in NMOSD in comparison to MS and HC. Comparison to MS and accounting for ON suggest this effect to be at least in part independent of ON. This supports a primary retinopathy in AQP4-IgG-seropositive NMOSD.
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Source
http://dx.doi.org/10.1212/NXI.0000000000000805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413713PMC
September 2020