113 results on '"Ludolph, Albert C."'
Search Results
2. Primary lateral sclerosis: application and validation of the 2020 consensus diagnostic criteria in an expert opinion-based PLS cohort
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Witzel, Simon, Micca, Veronika, Mu¨ller, Hans P, Huss, André, Bachhuber, Franziska, Dorst, Johannes, Lulé, Dorothée E, Tumani, Hayrettin, Kassubek, Jan, and Ludolph, Albert C
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BackgroundValidation of the 2020 consensus criteria for primary lateral sclerosis (PLS) is essential for their use in clinical practice and future trials.MethodsIn a large cohort of patients diagnosed with PLS by expert opinion prior to the new criteria with detailed clinical baseline evaluation (n=107) and longitudinal follow-up (n=63), we applied the new diagnostic criteria and analysed the clinical phenotype, electromyography (EMG), diagnostic accuracy and prognosis, adding neurofilaments and MRI as potential biomarkers.ResultsThe criteria for definite PLS were met by 28% and those for probable PLS by 19%, whereas 53% did not meet the full criteria at baseline, mainly due to the time, EMG and region criteria. Patients not meeting the criteria had less generalised upper motor neuron involvement but were otherwise similar in demographic and clinical characteristics. All patients with definite and probable PLS maintained PLS diagnosis during follow-up, while four patients not meeting the criteria developed clinical lower motor neuron involvement. Definite PLS cases showed improved survival compared with probable PLS and patients who did not meet the criteria. Despite a clinical PLS phenotype, fibrillation potentials/positive sharp waves and fasciculations in one or more muscles were a frequent EMG finding, with the extent and prognostic significance depending on disease duration. Serum neurofilament light and a multiparametric MRI fibre integrity Z-score correlated with clinical parameters and were identified as potential biomarkers.ConclusionValidation of the 2020 PLS consensus criteria revealed high diagnostic certainty and prognostic significance, supporting their value for research and clinical practice.
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- 2024
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3. AI-assisted automatic MRI-based tongue volume evaluation in motor neuron disease (MND)
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Vernikouskaya, Ina, Müller, Hans-Peter, Ludolph, Albert C., Kassubek, Jan, and Rasche, Volker
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Purpose: Motor neuron disease (MND) causes damage to the upper and lower motor neurons including the motor cranial nerves, the latter resulting in bulbar involvement with atrophy of the tongue muscle. To measure tongue atrophy, an operator independent automatic segmentation of the tongue is crucial. The aim of this study was to apply convolutional neural network (CNN) to MRI data in order to determine the volume of the tongue. Methods: A single triplanar CNN of U-Net architecture trained on axial, coronal, and sagittal planes was used for the segmentation of the tongue in MRI scans of the head. The 3D volumes were processed slice-wise across the three orientations and the predictions were merged using different voting strategies. This approach was developed using MRI datasets from 20 patients with ‘classical’ spinal amyotrophic lateral sclerosis (ALS) and 20 healthy controls and, in a pilot study, applied to the tongue volume quantification to 19 controls and 19 ALS patients with the variant progressive bulbar palsy (PBP). Results: Consensus models with softmax averaging and majority voting achieved highest segmentation accuracy and outperformed predictions on single orientations and consensus models with union and unanimous voting. At the group level, reduction in tongue volume was not observed in classical spinal ALS, but was significant in the PBP group, as compared to controls. Conclusion: Utilizing single U-Net trained on three orthogonal orientations with consequent merging of respective orientations in an optimized consensus model reduces the number of erroneous detections and improves the segmentation of the tongue. The CNN-based automatic segmentation allows for accurate quantification of the tongue volumes in all subjects. The application to the ALS variant PBP showed significant reduction of the tongue volume in these patients and opens the way for unbiased future longitudinal studies in diseases affecting tongue volume.
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- 2024
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4. Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries
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Logroscino, Giancarlo, Piccininni, Marco, Graff, Caroline, Hardiman, Orla, Ludolph, Albert C., Moreno, Fermin, Otto, Markus, Remes, Anne M., Rowe, James B., Seelaar, Harro, Solje, Eino, Stefanova, Elka, Traykov, Latchezar, Jelic, Vesna, Rydell, Melissa Taheri, Pender, Niall, Anderl-Straub, Sarah, Barandiaran, Myriam, Gabilondo, Alazne, Krüger, Johanna, Murley, Alexander G., Rittman, Timothy, van der Ende, Emma L., van Swieten, John C., Hartikainen, Päivi, Stojmenovic, Gorana Mandic, Mehrabian, Shima, Benussi, Luisa, Alberici, Antonella, Dell’Abate, Maria Teresa, Zecca, Chiara, and Borroni, Barbara
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IMPORTANCE: Diagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches. OBJECTIVE: To assess the incidence of FTLD across Europe. DESIGN, SETTING, AND PARTICIPANTS: The Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021. MAIN OUTCOMES AND MEASURES: Random-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity. RESULTS: Based on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057. CONCLUSIONS AND RELEVANCE: The findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.
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- 2023
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5. Tau-targeting antisense oligonucleotide MAPTRxin mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial
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Mummery, Catherine J., Börjesson-Hanson, Anne, Blackburn, Daniel J., Vijverberg, Everard G. B., De Deyn, Peter Paul, Ducharme, Simon, Jonsson, Michael, Schneider, Anja, Rinne, Juha O., Ludolph, Albert C., Bodenschatz, Ralf, Kordasiewicz, Holly, Swayze, Eric E., Fitzsimmons, Bethany, Mignon, Laurence, Moore, Katrina M., Yun, Chris, Baumann, Tiffany, Li, Dan, Norris, Daniel A., Crean, Rebecca, Graham, Danielle L., Huang, Ellen, Ratti, Elena, Bennett, C. Frank, Junge, Candice, and Lane, Roger M.
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Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPTexpression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRxor placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRxpharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRxand 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRxgroups. Clinicaltrials.gov registration number: NCT03186989.
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- 2023
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6. Blood β-Synuclein and Neurofilament Light Chain During the Course of Prion Disease.
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Halbgebauer, Steffen, Abu-Rumeileh, Samir, Oeckl, Patrick, Steinacker, Petra, Roselli, Francesco, Wiesner, Diana, Mammana, Angela, Beekes, Michael, Kortazar-Zubizarreta, Izaro, Perez de Nanclares, Guiomar, Capellari, Sabina, Giese, Armin, Castilla, Joaquin, Ludolph, Albert C., Zakova, Dana, Parchi, Piero, Otto, Markus, and Žáková, Dana
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- 2022
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7. FRONTotemporal dementia Incidence European Research Study—FRONTIERS: Rationale and design.
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Borroni, Barbara, Graff, Caroline, Hardiman, Orla, Ludolph, Albert C., Moreno, Fermin, Otto, Markus, Piccininni, Marco, Remes, Anne M, Rowe, James B, Seelaar, Harro, Stefanova, Elka, Traykov, Latchezar, and Logroscino, Giancarlo
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Introduction: The incidence of Frontotemporal Lobar Degeneration (FTLD)–related disorders and their characteristics are not well known. The "FRONTotemporal dementia Incidence European Research Study" (FRONTIERS) is designed to fill this gap. Methods: FRONTIERS is a European prospective, observational population study based on multinational registries. FRONTIERS comprises 11 tertiary referral centers across Europe with long‐lasting experience in FTLD‐related disorders and comprehensive regional referral networks, enabling incidence estimation over well‐defined geographical areas. Endpoints: The primary endpoints are (1) the incidence of FTLD‐related disorders across Europe; (2) geographic trends of FTLD‐related disorders; (3) the distribution of FTLD phenotypes in different populations and ethnicities in Europe; (4) inheritance of FTLD‐related disorders, including the frequencies of monogenic FTLD as compared to overall disease burden; and (5) implementation of data banking for clinical and biological material. Expected impacts: FRONTIERS will improve the understanding of FTLD‐related disorders and their epidemiology, promoting appropriate public health service policies and treatment strategies. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Life Course of Physical Activity and Risk and Prognosis of Amyotrophic Lateral Sclerosis in a German ALS Registry.
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Rosenbohm, Angela, Peter, Raphael, Dorst, Johannes, Kassubek, Jan, Rothenbacher, Dietrich, Nagel, Gabriele, Ludolph, Albert C., and ALS Registry Swabia Study Group
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- 2021
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9. Blood β-Synuclein and Neurofilament Light Chain During the Course of Prion Disease
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Halbgebauer, Steffen, Abu-Rumeileh, Samir, Oeckl, Patrick, Steinacker, Petra, Roselli, Francesco, Wiesner, Diana, Mammana, Angela, Beekes, Michael, Kortazar-Zubizarreta, Izaro, Perez de Nanclares, Guiomar, Capellari, Sabina, Giese, Armin, Castilla, Joaquin, Ludolph, Albert C., Žáková, Dana, Parchi, Piero, and Otto, Markus
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- 2022
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10. Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis
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Witzel, Simon, Maier, André, Steinbach, Robert, Grosskreutz, Julian, Koch, Jan C., Sarikidi, Anastasia, Petri, Susanne, Günther, René, Wolf, Joachim, Hermann, Andreas, Prudlo, Johannes, Cordts, Isabell, Lingor, Paul, Löscher, Wolfgang N., Kohl, Zacharias, Hagenacker, Tim, Ruckes, Christian, Koch, Birgit, Spittel, Susanne, Günther, Kornelia, Michels, Sebastian, Dorst, Johannes, Meyer, Thomas, and Ludolph, Albert C.
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IMPORTANCE: Intravenous edaravone is approved as a disease-modifying drug for patients with amyotrophic lateral sclerosis (ALS), but evidence for efficacy is limited to short-term beneficial effects shown in the MCI186-ALS19 study in a subpopulation in which efficacy was expected. OBJECTIVE: To evaluate the long-term safety and effectiveness of intravenous edaravone therapy for patients with ALS in a real-world clinical setting. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, propensity score–matched cohort study conducted between June 2017 and March 2020 at 12 academic ALS referral centers associated with the German Motor Neuron Disease Network. Of 1440 patients screened, 738 were included in propensity score matching. Final analyses included 324 patients with ALS comprising 194 patients who started intravenous edaravone treatment (141 received ≥4 consecutive treatment cycles; 130 matched) and 130 propensity score–matched patients with ALS receiving standard therapy. All patients had probable or definite ALS according to the El Escorial criteria, with disease onset between December 2012 and April 2019. Subgroups were defined by applying the MCI186-ALS19 study inclusion criteria to evaluate whether patients would have been considered eligible (EFAS) or ineligible (non-EFAS). EXPOSURES: Intravenous edaravone plus riluzole vs riluzole only. MAIN OUTCOMES AND MEASURES: Patient characteristics and systematic safety assessment for patients who received at least 1 dose of intravenous edaravone. Effectiveness assessment of edaravone was conducted among patients who received at least 4 treatment cycles compared with propensity score–matched patients with ALS who received only standard therapy. Primary outcome was disease progression measured by decrease in the ALS Functional Rating Scale–Revised (ALSFRS-R) score. Secondary outcomes were survival probability, time to ventilation, and change in disease progression before vs during treatment. To account for the matched design, patients receiving edaravone and their corresponding matched controls were regarded as related samples in disease progression analyses; stratification for propensity score quintiles was used for survival probability and time to ventilation analyses. RESULTS: A total of 194 patients started intravenous edaravone treatment; 125 (64%) were male, and the median age was 57.5 years (IQR, 50.7-63.8 years). Potential adverse effects were observed in 30 cases (16%), most notably infections at infusion sites and allergic reactions. Disease progression among 116 patients treated for a median of 13.9 months (IQR, 8.9-13.9 months) with edaravone did not differ from 116 patients treated for a median of 11.2 months (IQR, 6.4-20.0 months) with standard therapy (ALSFRS-R points/month, −0.91 [95% CI, −0.69 to −1.07] vs −0.85 [95% CI, −0.66 to −0.99]; P = .37). No significant differences were observed in the secondary end points of survival probability, time to ventilation, and change in disease progression. Similarly, outcomes between patients treated with edaravone and matched patients did not differ within the EFAS and non-EFAS subgroups. CONCLUSIONS AND RELEVANCE: This cohort study using propensity score matching found that, although long-term intravenous edaravone therapy for patients with ALS was feasible and mainly well tolerated, it was not associated with any disease-modifying benefit. Intravenous edaravone may not provide a clinically relevant additional benefit compared with standard therapy alone.
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- 2022
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11. An observational study on quality of life and preferences to sustain life in locked-in state.
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Kuzma-Kozakiewicz, Magdalena MD, Andersen, Peter M. MD, Ciecwierska, Katarzyna MD, Vazquez, Cynthia, Helczyk, Olga, Loose, Markus, Uttner, Ingo PhD, Ludolph, Albert C. MD, Lule, Dorothee PhD, Kuzma-Kozakiewicz, Magdalena, Andersen, Peter M, Ciecwierska, Katarzyna, Vázquez, Cynthia, Uttner, Ingo, Ludolph, Albert C, and Lulé, Dorothée
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- 2019
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12. Comparison of CSF and serum neurofilament light and heavy chain as differential diagnostic biomarkers for ALS
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Halbgebauer, Steffen, Steinacker, Petra, Verde, Federico, Weishaupt, Jochen, Oeckl, Patrick, von Arnim, Christine, Dorst, Johannes, Feneberg, Emily, Mayer, Benjamin, Rosenbohm, Angela, Silani, Vincenzo, Ludolph, Albert C, and Otto, Markus
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ObjectiveElevated levels of neurofilament light (NfL) and heavy (NfH) chain in amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) and serum reflect neuro-axonal degeneration and are used as diagnostic biomarkers. However, studies comparing the differential diagnostic potential for ALS of all four parameters are missing. Here, we measured serum NfL/NfH and CSF NfL/NfH in a large cohort of ALS and other neurological disorders and analysed the differential diagnostic potential.MethodsIn total CSF and serum of 294 patients were analysed. The diagnostic groups comprised: ALS (n=75), frontotemporal lobar degeneration (FTLD) (n=33), Alzheimer’s disease (n=20), Parkinson’s disease (dementia) (n=18), Creutzfeldt-Jakob disease (n=11), non-neurodegenerative controls (n=77) (Con) and 60 patients who were seen under the direct differential diagnosis of a patient with ALS (Con.DD).ResultsCSF and serum NfL and NfH showed significantly increased levels in ALS (p<0.0001) compared with Con and Con.DD. The difference between ALS and FTLD was markedly stronger for NfH than for NfL. CSF and serum NfL demonstrated a stronger correlation (r=0.84 (95% CI 0.80 to 0.87), p<0.001) than CSF and serum NfH (r=0.68 (95% CI 0.61 to 0.75), p<0.0001). Comparing ALS and Con.DD, receiver operating characteristic analysis revealed the best area under the curve (AUC) value for CSF NfL (AUC=0.94, 95% CI 0.91 to 0.98), followed by CSF NfH (0.93, 95% CI 0.88 to 0.98), serum NfL (0.93, 95% CI 0.89 to 0.97) and serum NfH (0.88, 95% CI 0.82 to 0.94).ConclusionOur results demonstrate that CSF NfL and NfH as well as serum NfL are equally suited for the differential diagnosis of ALS, whereas serum NfH appears to be slightly less potent.
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- 2022
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13. Fat-rich versus carbohydrate-rich nutrition in ALS: a randomised controlled study
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Dorst, Johannes, Doenz, Judith, Kandler, Katharina, Dreyhaupt, Jens, Tumani, Hayrettin, Witzel, Simon, Schuster, Joachim, and Ludolph, Albert C
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ObjectiveThere is growing evidence that the course of amyotrophic lateral sclerosis (ALS) may be influenced beneficially by applying high-caloric food supplements (HCSs). However, it is unknown which composition of nutrients offers optimal tolerability and weight gain.MethodsWe conducted a randomised controlled study (Safety and Tolerability of Ultra-high-caloric Food Supplements in Amyotrophic Lateral Sclerosis (ALS); TOLCAL-ALS study) in 64 patients with possible, probable or definite ALS according to El Escorial criteria. Patients were randomised into four groups: a high-caloric fatty supplement (HCFS; 405 kcal/day, 100% fat), an ultra-high-caloric fatty supplement (UHCFS; 810 kcal/day, 100% fat), an ultra-high-caloric, carbohydrate-rich supplement (UHCCS; 900 kcal/day, 49% carbohydrates) and an open control (OC) group without any supplement. The primary endpoint was tolerability. Patients were followed up over 4 weeks.ResultsGastrointestinal side effects were most frequent in the UHCFS group (75.0%), while loss of appetite was most frequent in the UHCCS group (35.3%). During intervention, patients gained +0.9 kg/month of body weight (IQR −0.9 to 1.5; p=0.03) in the HCFS group and +0.9 kg/month (IQR −0.8 to 2.0; p=0.05) in the UHCFS group. A non-significant trend for weight gain (+0.6 kg/month (IQR −0.3 to 1.9; p=0.08)) was observed in the UHCCS group. Patients in OC group continued to lose body weight (−0.5 kg/month, IQR −1.4 to 1.3; p=0.42).InterpretationThe findings suggest that HCSs frequently cause mild to moderate tolerability issues in patients with ALS, most notably gastrointestinal symptoms in high-fat supplements, and loss of appetite in high-carbohydrate supplements. All three HCSs tested are suited to increase body weight.
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- 2022
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14. CSF levels of SNAP-25 are increased early in Creutzfeldt-Jakob and Alzheimer’s disease
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Halbgebauer, Steffen, Steinacker, Petra, Hengge, Sophie, Oeckl, Patrick, Abu Rumeileh, Samir, Anderl-Straub, Sarah, Lombardi, Jolina, Von Arnim, Christine A F, Giese, Armin, Ludolph, Albert C, and Otto, Markus
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BackgroundSynaptosomal-associated protein 25 (SNAP-25) in cerebrospinal fluid (CSF) is an emerging synaptic biomarker for the early diagnosis of Alzheimer’s disease (AD). However, comprehensive studies investigating the marker in Creutzfeldt-Jakob disease (CJD) and in the differential diagnosis of neurodegenerative diseases are still lacking.MethodsWe developed a novel, sensitive ELISA for the measurement of SNAP-25 in CSF. In total, we analysed 316 patients from 6 diagnostic groups comprising patients with AD (n=96), CJD (n=55), Parkinson’s disease spectrum (n=41), frontotemporal lobar degeneration (n=25) and amyotrophic lateral sclerosis (n=24) and non-neurodegenerative control patients (n=75). Using receiver operating characteristic curve analysis, we analysed the differential diagnostic potential and compared the results with core AD biomarkers.ResultsSNAP-25 CSF concentrations were elevated in AD and CJD (p<0.0001) but not in the other neurodegenerative diseases. Increased levels were observed already at early AD and CJD stages (p<0.0001). In CJD, SNAP-25 levels correlated negatively with survival time (r=−0.33 (95% CI −0.57 to −0.04, p=0.02). For the discrimination of AD from all other diseases except CJD, we observed a good diagnostic performance for CSF SNAP-25 (area under the curve (AUC) 0.85) which was further improved by applying the ratio with CSF amyloid-β 1–42 (AUC 0.95). For CJD, we could demonstrate a strong differential diagnostic potential against all other groups including AD (AUC 0.97).ConclusionUsing the novel established CSF SNAP-25 ELISA, we here demonstrate the applicability of SNAP-25 as an early synaptic biomarker for both AD and CJD with a possible prognostic value in patients with CJD.
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- 2022
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15. Serum GFAP differentiates Alzheimer’s disease from frontotemporal dementia and predicts MCI-to-dementia conversion
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Oeckl, Patrick, Anderl-Straub, Sarah, Von Arnim, Christine A F, Baldeiras, Inês, Diehl-Schmid, Janine, Grimmer, Timo, Halbgebauer, Steffen, Kort, Anna M, Lima, Marisa, Marques, Tainá M, Ortner, Marion, Santana, Isabel, Steinacker, Petra, Verbeek, Marcel M, Volk, Alexander E, Ludolph, Albert C, and Otto, Markus
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ObjectiveReactive astrogliosis is a hallmark of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD).MethodsThis multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple).ResultsIn total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276–505 pg/mL) compared with controls (167 pg/mL, IQR 108–234 pg/mL) and bvFTD (190 pg/mL, IQR 134–298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232–433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253–414 pg/mL vs 215 pg/mL, IQR 111–266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8).ConclusionsOur data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.
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- 2022
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16. De novo mutations in SOD1are a cause of ALS
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Mu¨ller, Kathrin, Oh, Ki-Wook, Nordin, Angelica, Panthi, Sudhan, Kim, Seung Hyun, Nordin, Frida, Freischmidt, Axel, Ludolph, Albert C, Ki, Chang Seok, Forsberg, Karin, Weishaupt, Jochen, Kim, Young-Eun, and Andersen, Peter Munch
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ObjectiveThe only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1as a cause of ALS.MethodsWe analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.ResultsWe identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved.ConclusionsDe novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.
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- 2022
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17. Clinicoanatomical substrates of selfish behaviour in amyotrophic lateral sclerosis – An observational cohort study
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Lulé, Dorothée, Michels, Sebastian, Finsel, Julia, Braak, Heiko, Del Tredici, Kelly, Strobel, Joachim, Beer, Ambros J., Uttner, Ingo, Müller, Hans-Peter, Kassubek, Jan, Juengling, Freimut D., and Ludolph, Albert C.
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ALS primarily affects motor functions, but cognitive functions, including social understanding, may also be impaired. Von Economo neurons (VENs) are part of the neuronal substrate of social understanding and these cells are histopathologically altered in ALS. We investigated whether activity in areas including VENs is associated with an impairment of cognitive tasks that mirror social functioning.
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- 2022
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18. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
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van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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- 2021
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19. Life Course of Physical Activity and Risk and Prognosis of Amyotrophic Lateral Sclerosis in a German ALS Registry
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Rosenbohm, Angela, Peter, Raphael, Dorst, Johannes, Kassubek, Jan, Rothenbacher, Dietrich, Nagel, Gabriele, Ludolph, Albert C., Andres, Frank, Arnold, Guy, Baier, Hartmut, Baezner, Hansjoerg, Beattie, James, Behne, Friedrich, Bengel, Dietmar, Boertlein, Axel, Vera, Bracknies, Alber, Burkhard, Buttmann, Mathias, Dempewolf, Silke, Dettmers, Christian, Freund, Wolfgang, Gasser, Thomas, Gold, Hans-Juergen, Hamann, Gerhard, Hecht, Martin, Heimbach, Bernhard, Herting, Birgit, Huber, Roman, Huelser, Paul-Juergen, HuberHartmann, Karlheinz, Jüttler, Eric, Kaspar, Attila, Kern, Rolf, Kimmig, Hubert, Christof, Klötzsch, Chatzikonstantinou, Anastasios, Klopstock, Thomas, Kohler, Andreas, Lichy, Christoph, Lindner, Alfred, Lingor, Paul, Lulé, Dorothee, Metrikat, Jens, Meudt, Oliver, Meyer, Andreas, Naegele, Andrea, Naumann, Markus, Neher, Klaus-Dieter, Neuhaus, Oliver, Neusch, Clemens, Niehaus, Ludwig, Raape, Jan, Ratzka, Peter, Reinhard, Matthias, Rothmeier, Johann, Sabolek, Michael, Schabet, Martin, SchaeffVogelsang, MDMario, Schell, Caroline, Schell, Caroline, Schweigert, Barbara, Sommer, Norbert, Stroick, Mark, Synofzik, Mathis, Tumani, Hayrettin, Volkmann, Jens, Weiler, Markus, Wick, Wolfgang, Opherk, Christian, Weiller, Cornelius, Zeller, Daniel, Baumgärtner, Jessica, Born, Christoph, Bürgy, Martin, Connemann, Bernhard, Etzersdorfer, Elmar, Friederich, Hubertus, Gahr, Maximilian, Gogolkiewicz, Alex, Greber, Ralf, Gebhardt, Jochen, Grunze, Heinz, Henkel, Karsten, Hewer, Walter, Raether, Andreas, Joos, Andreas, Köhler, Matthias, Kozian, Ralf, Laske, Christoph, Michaelides, Alexandros, Munk, Matthias, Niestroj, Andreas, Schmauss, Max, Schmauss, Max, SchoenebergerStroick, Katrin, Schoerner, Kai-Uwe, Spannhorst, Stefan, Steber, Raimund, Thomas, Christine, and Vasic, Nenad
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- 2021
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20. Patient-reported outcome parameters and disability worsening in progressive multiple sclerosis.
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Abdelhak, Ahmed, Antweiler, Kai, Kowarik, Markus C., Senel, Makbule, Havla, Joachim, Zettl, Uwe K., Kleiter, Ingo, Hoshi, Muna-Miriam, Skripuletz, Thomas, Haarmann, Axel, Stahmann, Alexander, Huss, Andre, Gingele, Stefan, Krumbholz, Markus, Selge, Charlotte, Friede, Tim, Ludolph, Albert C., Overell, James, Koendgen, Harold, and Clinch, Susanne
- Abstract
• In two well-characterized progressive multiple sclerosis (PMS) cohorts, depression, fatigue, and quality of life metrics were worse in people with PMS who experienced disability progression. • In addition, worse performance in scores reflecting physical limitation on quality of life was associated with a higher likelihood of coincident and future diagnosis of disability progression independent of relapse activity. • PROMs could support monitoring disability progression in people with PMS through practical, cost-efficient, and remotely accessible patient-centered feedback. Detection and prediction of disability progression is a significant unmet need in people with progressive multiple sclerosis (PwPMS). Government and health agencies have deemed the use of patient-reported outcomes measurements (PROMs) in clinical practice and clinical trials a major strategic priority. Nevertheless, data documenting the clinical utility of PROMs in neurological diseases is scarce. This study evaluates if assessment of PROMs could track progression in PwPMS. Emerging blood Biomarkers in Progressive Multiple Sclerosis (EmBioProMS) investigated PROMs (Beck depression inventory-II (BDI-II), multiple sclerosis impact scale-29 (MSIS-29), fatigue scale for motor and cognition (FSMC)) in PwPMS (primary [PPMS] and secondary progressive MS [SPMS]). PROMs were evaluated longitudinally and compared between participants with disability progression (at baseline; retrospective evidence of disability progression (EDP), and during follow up (FU); prospective evidence of confirmed disability progression (CDP)) and those without progression. In an independent cohort of placebo participants of the phase III ORATORIO trial in PPMS, the diagnostic and prognostic value of another PROMs score (36-Item Short Form Survey [SF-36]) regarding CDP was evaluated. EmBioProMS participants with EDP in the two years prior to inclusion (n = 136/227), or who suffered from CDP during FU (number of events= 88) had worse BDI-II, MSIS-29, and FSMC scores compared to PwPMS without progression. In addition, baseline MSIS29 physical above 70th, 80th, and 90th percentiles predicted future CDP/ progression independent of relapse activity in EmBioProMS PPMS participants (HR of 3.7, 6.9, 6.7, p = 0.002, <0.001, and 0.001, respectively). In the placebo arm of ORATORIO (n = 137), the physical component score (PCS) of SF-36 worsened at week 120 compared to baseline, in cases who experienced progression over the preceding trial period (P = 0.018). Worse PCS at baseline was associated with higher hazard ratios of disability accumulation over the subsequent 120 weeks (HR: 2.01 [30
th- ], 2.11 [20th- ], and 2.8 [10th percentile], P = 0.007, 0.012 and 0.005, respectively). PROMs could provide additional, practical, cost-efficient, and remotely accessible insight about disability progression in PMS through standardized, structured, and quantifiable patient feedback. [ABSTRACT FROM AUTHOR]- Published
- 2024
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21. Clinico-genetic findings in 509 frontotemporal dementia patients
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Wagner, Matias, Lorenz, Georg, Volk, Alexander E., Brunet, Theresa, Edbauer, Dieter, Berutti, Riccardo, Zhao, Chen, Anderl-Straub, Sarah, Bertram, Lars, Danek, Adrian, Deschauer, Marcus, Dill, Veronika, Fassbender, Klaus, Fliessbach, Klaus, Götze, Katharina S., Jahn, Holger, Kornhuber, Johannes, Landwehrmeyer, Bernhard, Lauer, Martin, Obrig, Hellmuth, Prudlo, Johannes, Schneider, Anja, Schroeter, Matthias L., Uttner, Ingo, Vukovich, Ruth, Wiltfang, Jens, Winkler, Andrea S., Zhou, Qihui, Ludolph, Albert C., Oexle, Konrad, Otto, Markus, Diehl-Schmid, Janine, and Winkelmann, Juliane
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Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72(n= 47), GRN(n= 26), MAPT(n= 11), TBK1(n= 5), FUS(n= 1), TARDBP(n= 1), and CTSF(n= 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSFas an FTD gene. ABCA7was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPTpatients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.
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- 2021
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22. Beta-synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer’s disease
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Halbgebauer, Steffen, Oeckl, Patrick, Steinacker, Petra, Yilmazer-Hanke, Deniz, Anderl-Straub, Sarah, von Arnim, Christine, Froelich, Lutz, Gomes, Luis Aragão, Hausner, Lucrezia, Huss, Andre, Jahn, Holger, Weishaupt, Jochen, Ludolph, Albert C, Thal, Dietmar R, and Otto, Markus
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ObjectiveSynaptic loss plays a major role in Alzheimer’s disease (AD). However so far no neurochemical marker for synaptic loss has been introduced into clinical routine. By mass spectrometry beta-synuclein was established as a candidate marker. We now aimed to set up a novel ELISA for beta-synuclein for evaluation of its potential as a diagnostic and predictive marker for AD.MethodsWe analysed in total 393 patients from four specialised centres. The diagnostic groups comprised: AD (n=151), behavioural variant frontotemporal dementia (bvFTD, n=18), Parkinson syndrome (n=46), Creutzfeldt-Jakob disease (CJD, n=23), amyotrophic lateral sclerosis (ALS, n=29), disease control (n=66) and 60 non-neurodegenerative control patients. Results were compared with core AD biomarkers (total tau, phospho-tau and amyloid-β peptide 1–42). Additionally, coexistence of beta-synuclein with vesicular glutamate transporter 1 (VGLUT1) was determined and beta-synuclein levels were quantified in brain homogenates.ResultsBeta-synuclein levels quantified with the newly established ELISA correlated strongly with antibody-free quantitative mass spectrometry data (r=0.92 (95% CI: 0.89 to 0.94), p<0.0001). Cerebrospinal fluid (CSF) beta-synuclein levels were increased in AD-mild cognitive impairment (p<0.0001), AD dementia (p<0.0001) and CJD (p<0.0001), but not in bvFTD, Parkinson syndrome or ALS. Furthermore, beta-synuclein was localised in VGLUT1-positive glutamatergic synapses, and its expression was significantly reduced in brain tissue from patients with AD (p<0.01).ConclusionWe successfully established a sensitive and robust ELISA for the measurement of brain-enriched beta-synuclein, which we could show is localised in glutamatergic synapses. We confirmed previous, mass spectrometry-based observations of increased beta-synuclein levels in CSF of patients with AD and CJD supporting its potential use as a marker of synaptic degeneration.
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- 2021
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23. Phenotyping of the thoracic-onset variant of amyotrophic lateral sclerosis
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Kandler, Katharina, Witzel, Simon, Eder, Konstantin, Rothenbacher, Dietrich, Nagel, Gabriele, Peter, Raphael S, Schuster, Joachim, Dorst, Johannes, Rosenbohm, Angela, and Ludolph, Albert C
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- 2022
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24. Fabry Disease With Concomitant Lewy Body Disease.
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Del Tredici, Kelly, Ludolph, Albert C, Feldengut, Simone, Jacob, Christian, Reichmann, Heinz, Bohl, Jürgen R, and Braak, Heiko
- Abstract
Although Gaucher disease can be accompanied by Lewy pathology (LP) and extrapyramidal symptoms, it is unknown if LP exists in Fabry disease (FD), another progressive multisystem lysosomal storage disorder. We aimed to elucidate the distribution patterns of FD-related inclusions and LP in the brain of a 58-year-old cognitively unimpaired male FD patient suffering from predominant hypokinesia. Immunohistochemistry (CD77, α-synuclein, collagen IV) and neuropathological staging were performed on 100-µm sections. Tissue from the enteric or peripheral nervous system was unavailable. As controls, a second cognitively unimpaired 50-year-old male FD patient without LP or motor symptoms and 3 age-matched individuals were examined. Inclusion body pathology was semiquantitatively evaluated. Although Lewy neurites/bodies were not present in the 50-year-old individual or in controls, severe neuronal loss in the substantia nigra pars compacta and LP corresponding to neuropathological stage 4 of Parkinson disease was seen in the 58-year-old FD patient. Major cerebrovascular lesions and/or additional pathologies were absent in this individual. We conclude that Lewy body disease with parkinsonism can occur within the context of FD. Further studies determining the frequencies of both inclusion pathologies in large autopsy-controlled FD cohorts could help clarify the implications of both lesions for disease pathogenesis, potential spreading mechanisms, and therapeutic interventions.
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- 2020
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25. Targeted Mass Spectrometry Suggests Beta-Synuclein as Synaptic Blood Marker in Alzheimer’s Disease
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Oeckl, Patrick, Halbgebauer, Steffen, Anderl-Straub, Sarah, von Arnim, Christine A. F., Diehl-Schmid, Janine, Froelich, Lutz, Grimmer, Timo, Hausner, Lucrezia, Denk, Johannes, Jahn, Holger, Steinacker, Petra, Weishaupt, Jochen H., Ludolph, Albert C., and Otto, Markus
- Abstract
Synaptic degeneration is a major hallmark of Alzheimer’s disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read-out for patient diagnosis and possible follow-up in clinical trials. Several synaptic markers for AD are described in cerebrospinal fluid (CSF), but studies in blood have failed so far. Using quantitative mass spectrometry (IP-MS, MRM) we observed increased concentrations of the presynaptic protein beta-synuclein (βSyn) in CSF and blood of AD patients (n= 64, p< 0.01) and confirmed this finding in two validation cohorts (AD: n= 40 and n= 49, controls: n= 44 and n= 25). βSyn was already increased in patients with mild cognitive impairment (p< 0.01) and was also markedly increased in Creutzfeldt–Jakob disease (CJD; n= 25, p< 0.001) but not behavioral variant frontotemporal dementia (n= 16), dementia with Lewy bodies/Parkinson’s disease dementia (n= 13), Parkinson’s disease (n= 25), or amyotrophic lateral sclerosis (n= 30). The diagnostic sensitivity and specificity for CJD versus other neurodegenerative diseases was ≥96%. These findings suggest βSyn as a candidate blood marker for synaptic degeneration that might be used in clinical AD trials and patient follow-up as part of the recently suggested ATN biomarker panel. It can also serve in the differential diagnosis of CJD.
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- 2020
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26. Deficits in verbal fluency in presymptomatic C9orf72mutation gene carriers—a developmental disorder
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Lulé, Dorothée E, Mu¨ller, Hans-Peter, Finsel, Julia, Weydt, Patrick, Knehr, Antje, Winroth, Ivar, Andersen, Peter, Weishaupt, Jochen, Uttner, Ingo, Kassubek, Jan, and Ludolph, Albert C
- Abstract
BackgroundA mutation in C9orf72constitute a cross-link between amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). At clinical manifestation, both patient groups may present with either cognitive impairment of predominantly behaviour or language (in FTD) or motor dysfunctions (in ALS).MethodsIn total, 36 non-symptomatic mutation carriers from ALS or FTD families were examined, including 21 subjects with C9orf72and 15 with SOD1mutations. Data were compared with 91 age-matched, education-matched and gender-matched healthy subjects (56 were first-degree relatives from ALS or FTD families, 35 with no known family history of ALS/FTD). MRI scanning for diffusion tensor imaging was performed to map fractional anisotropy (FA). Subjects performed an extensive neuropsychological assessment to address verbal fluency, language, executive, memory and visuospatial function. Measurements were repeated after 12 months.ResultsC9orf72expansion carriers performed significantly worse in verbal fluency and non-verbal memory and presented with distinct alterations in structural white matter integrity indicated by lower FA values in inferior and orbitofrontal cortical areas compared with carriers of SOD1mutations or healthy subjects. Loss of structural integrity was associated with decreased verbal fluency performance. White matter alterations and cognitive performance showed no changes over 12 months in all subjects.DiscussionReduced verbal fluency performance seems to be a distinct clinical feature of C9orf72carriers before symptomatic disease onset without evidence for change over time in our cohort. The results support the emerging hypothesis of a general disorder in development in addition to neurodegeneration in C9orf72carriers.
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- 2020
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27. Author Correction: Tau-targeting antisense oligonucleotide MAPTRxin mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial
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Mummery, Catherine J., Börjesson-Hanson, Anne, Blackburn, Daniel J., Vijverberg, Everard G. B., De Deyn, Peter Paul, Ducharme, Simon, Jonsson, Michael, Schneider, Anja, Rinne, Juha O., Ludolph, Albert C., Bodenschatz, Ralf, Kordasiewicz, Holly, Swayze, Eric E., Fitzsimmons, Bethany, Mignon, Laurence, Moore, Katrina M., Yun, Chris, Baumann, Tiffany, Li, Dan, Norris, Daniel A., Crean, Rebecca, Graham, Danielle L., Huang, Ellen, Ratti, Elena, Bennett, C. Frank, Junge, Candice, and Lane, Roger M.
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- 2024
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28. Patient-reported outcome parameters and disability worsening in progressive multiple sclerosis
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Abdelhak, Ahmed, Antweiler, Kai, Kowarik, Markus C., Senel, Makbule, Havla, Joachim, Zettl, Uwe K., Kleiter, Ingo, Hoshi, Muna-Miriam, Skripuletz, Thomas, Haarmann, Axel, Stahmann, Alexander, Huss, Andre, Gingele, Stefan, Krumbholz, Markus, Selge, Charlotte, Friede, Tim, Ludolph, Albert C., Overell, James, Koendgen, Harold, Clinch, Susanne, Wang, Qing, Ziemann, Ulf, Hauser, Stephen L., Kümpfel, Tania, Green, Ari J, and Tumani, Hayrettin
- Abstract
•In two well-characterized progressive multiple sclerosis (PMS) cohorts, depression, fatigue, and quality of life metrics were worse in people with PMS who experienced disability progression.•In addition, worse performance in scores reflecting physical limitation on quality of life was associated with a higher likelihood of coincident and future diagnosis of disability progression independent of relapse activity.•PROMs could support monitoring disability progression in people with PMS through practical, cost-efficient, and remotely accessible patient-centered feedback.
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- 2024
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29. Mitochondrial genome study in blood of maternally inherited ALS cases
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Brockmann, Sarah J., Buck, Eva, Casoli, Tiziana, Meirelles, João L., Ruf, Wolfgang P., Fabbietti, Paolo, Holzmann, Karlheinz, Weishaupt, Jochen H., Ludolph, Albert C., Conti, Fiorenzo, and Danzer, Karin M.
- Abstract
Background: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. Results: We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. Conclusion: Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer’s and Parkinson’s diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.
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- 2023
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30. NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons.
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Higelin, Julia, Catanese, Alberto, Semelink-Sedlacek, Lena Luisa, Oeztuerk, Sertap, Lutz, Anne-Kathrin, Bausinger, Julia, Barbi, Gotthold, Speit, Günter, Andersen, Peter M., Ludolph, Albert C., Demestre, Maria, and Boeckers, Tobias M.
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Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction. Motoneurons carrying a C9orf72 mutation exhibited cell specific signs of increased DNA damage. This phenotype was even more severe in NEK1 c.2434A>T neurons that showed significantly increased DNA damage at basal level and impaired DDR after induction of DNA damage in an maturation-dependent manner. Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS. Therefore, our study contributes to the development of novel therapeutic strategies to reduce DNA damage accumulation in neurodegenerative diseases and ALS. [ABSTRACT FROM AUTHOR]
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- 2018
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31. Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation
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Catanese, Alberto, Olde Heuvel, Florian, Mulaw, Medhanie, Demestre, Maria, Higelin, Julia, Barbi, Gotthold, Freischmidt, Axel, Weishaupt, Jochen H., Ludolph, Albert C., Roselli, Francesco, and Boeckers, Tobias M.
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ABSTRACTMutations in the TBK1(TANK binding kinase 1) gene are causally linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TBK1 phosphorylates the cargo receptors OPTN and SQSTM1 regulating a critical step in macroautophagy/autophagy. Disruption of the autophagic flux leads to accumulation of cytosolic protein aggregates, which are a hallmark of ALS. hiPSC-derived TBK1-mutant motoneurons (MNs) showed reduced TBK1 levels and accumulation of cytosolic SQSTM1-positive aggresomes. By screening a library of nuclear-receptor-agonists for modifiers of the SQSTM1 aggregates, we identified 4-hydroxy(phenyl)retinamide (4HPR) as a potent modifier exerting detrimental effects on mutant-TBK1 motoneurons fitness exacerbating the autophagy overload. We have shown by TEM that TBK1-mutant motoneurons accumulate immature phagophores due a failure in the elongation phase, and 4HPR further worsens the burden of dysfunctional phagophores. 4HPR-increased toxicity was associated with the upregulation of SQSTM1 in a context of strongly reduced ATG10, while rescue of ATG10 levels abolished 4HPR toxicity. Finally, we showed that 4HPR leads to a downregulation of ATG10 and to an accumulation of SQSTM1+aggresomes also in hiPSC-derived C9orf72-mutant motoneurons. Our data show that cultured human motoneurons harboring mutations in TBK1gene display typical ALS features, like decreased viability and accumulation of cytosolic SQSTM1-positive aggresomes. The retinoid 4HPR appears a strong negative modifier of the fitness of TBK1 and C9orf72-mutant MNs, through a pathway converging on the mismatch of initiated autophagy and ATG10 levels. Thus, autophagy induction appears not to be a therapeutic strategy for ALS unless the specific underlying pathway alterations are properly addressed.Abbreviations4HPR: 4-hydroxy(phenyl)retinamide; AKT: AKT1 serine/threonine kinase 1; ALS: amyotrophic lateral sclerosis; ATG: autophagy related; AVs: autophagic vesicle; C9orf72: chromosome 9 open reading frame 72; CASP3: caspase 3; CHAT: choline O-acetyltransferase; CYCS: cytochrome c, somatic; DIV: day in vitro; FTD: frontotemporal dementia; FUS: FUS RNA binding protein; GFP: green fluorescent protein; hiPSCs: human induced pluripotent stem cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MNs: motoneurons; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; RARA: retinoic acid receptor alpha; SLC18A3/VACHT: solute carrier family 18 (vesicular acetylcholine transporter), member 3; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; TEM: transmission electron microscopy
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- 2019
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32. Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging
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Albrecht, Franziska, Mueller, Karsten, Ballarini, Tommaso, Lampe, Leonie, Diehl-Schmid, Janine, Fassbender, Klaus, Fliessbach, Klaus, Jahn, Holger, Jech, Robert, Kassubek, Jan, Kornhuber, Johannes, Landwehrmeyer, Bernhard, Lauer, Martin, Ludolph, Albert C., Lyros, Epameinondas, Prudlo, Johannes, Schneider, Anja, Synofzik, Matthis, Wiltfang, Jens, Danek, Adrian, Otto, Markus, Anderl-Straub, Sarah, Brüggen, Katharina, Fischer, Marie, Förstl, Hans, Hammer, Anke, Homola, György, Just, Walter, Levin, Johannes, Marroquin, Nicolai, Marschhauser, Anke, Nagl, Magdalena, Oberstein, Timo, Polyakova, Maryna, Pellkofer, Hannah, Richter-Schmidinger, Tanja, Rossmeier, Carola, Schuemberg, Katharina, Semler, Elisa, Spottke, Annika, Steinacker, Petra, Thöne-Otto, Angelika, Uttner, Ingo, Zech, Heike, and Schroeter, Matthias L.
- Abstract
Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia.
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- 2019
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33. Amyotrophe Lateralsklerose – ein Update zu Diagnostik, Therapie und Forschung
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Witzel, Simon and Ludolph, Albert C.
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- 2019
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34. Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice
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Brenner, David, Sieverding, Kirsten, Bruno, Clara, Lüningschrör, Patrick, Buck, Eva, Mungwa, Simon, Fischer, Lena, Brockmann, Sarah J., Ulmer, Johannes, Bliederhäuser, Corinna, Philibert, Clémentine E., Satoh, Takashi, Akira, Shizuo, Boillée, Séverine, Mayer, Benjamin, Sendtner, Michael, Ludolph, Albert C., Danzer, Karin M., Lobsiger, Christian S., Freischmidt, Axel, and Weishaupt, Jochen H.
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Heterozygous loss-of-function mutations of TANK-binding kinase 1 (TBK1) cause familial ALS, yet downstream mechanisms of TBK1 mutations remained elusive. TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous Tbk1 deletion alone does not lead to signs of motoneuron degeneration or disturbed autophagy in mice during a 200-d observation period. Surprisingly, however, hemizygous deletion of Tbk1 inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked SOD1G93A, which represents a “second hit” that induces both neuroinflammation and proteostatic dysregulation. At the early stage, heterozygous Tbk1 deletion impairs autophagy in motoneurons and prepones both the clinical onset and muscular denervation in SOD1G93A/Tbk1+/− mice. At the late disease stage, however, it significantly alleviates microglial neuroinflammation, decelerates disease progression, and extends survival. Our results indicate a profound effect of TBK1 on brain inflammatory cells under pro-inflammatory conditions and point to a complex, two-edged role of TBK1 in SOD1-linked ALS.
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- 2019
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35. Story of the ALS-FTD continuum retold: rather two distinct entities
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Lulé, Dorothée E, Aho-O¨zhan, Helena E A, Vázquez, Cynthia, Weiland, Ulrike, Weishaupt, Jochen H, Otto, Markus, Anderl-Straub, Sarah, Semler, Elisa, Uttner, Ingo, and Ludolph, Albert C
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ObjectiveTo determine the evolution and profile of cognitive and behavioural deficits in amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) to disentangle the development of FTD in ALS and vice versa.MethodsIn a prospective design, cognitive and behavioural profiles of 762 patients with motor predominant ALS (flail arm/leg syndrome, primary lateral sclerosis, pseudobulbar palsy, ALS) and behavioural predominant FTD (bvFTD, ALS-FTD) were determined and caregivers of patients with ALS were asked on the evolution of behavioural symptoms. Data were compared with 49 healthy controls. Cognition was measured with the Edinburgh Cognitive and Behavioral ALS Screen.ResultsEvolution and features of cognitive profile of patients with motor predominant ALS were distinctly different from patients with behavioural FTD with regard to number and degree of affected cognitive domains. Also, in ALS mostly minus symptoms evolved after physical symptom onset whereas in ALS-FTD plus and minus symptoms were reported with an onset before physical degradation.ConclusionEvolution of cognitive and behavioural profile in patients with motor predominant ALS is distinctly different from those psychocognitive findings in patients with behavioural variant dementia. This may support the hypothesis that (possibly genetic) triggers decide in the preclinical phase on either motor or psychocognitive phenotypes.
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- 2019
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36. Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage
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Spru¨gel, Maximilian I, Sembill, Jochen A, Kuramatsu, Joji B, Gerner, Stefan T, Hagen, Manuel, Roeder, Sebastian S, Endres, Matthias, Haeusler, Karl Georg, Sobesky, Jan, Schurig, Johannes, Zweynert, Sarah, Bauer, Miriam, Vajkoczy, Peter, Ringleb, Peter Arthur, Purrucker, Jan Christoph, Rizos, Timolaos, Volkmann, Jens, Muellges, Wolfgang, Kraft, Peter, Schubert, Anna-Lena, Erbguth, Frank, Nueckel, Martin, Schellinger, Peter D, Glahn, Jo¨rg, Knappe, Ulrich J, Fink, Gereon Rudolf, Dohmen, Christian, Stetefeld, Henning, Fisse, Anna Lena, Minnerup, Jens, Hagemann, Georg, Rakers, Florian, Reichmann, Heinz, Schneider, Hauke, Wo¨pking, Sigrid, Ludolph, Albert C, Sto¨sser, Sebastian, Neugebauer, Hermann, Ro¨ther, Joachim, Michels, Peter, Schwarz, Michael, Reimann, Gernot, Ba¨zner, Hansjo¨rg, Schwert, Henning, Classen, Joseph, Michalski, Dominik, Grau, Armin, Palm, Frederick, Urbanek, Christian, Wo¨hrle, Johannes C, Alshammari, Fahid, Horn, Markus, Bahner, Dirk, Witte, Otto W, Guenther, Albrecht, Hamann, Gerhard F, Lu¨cking, Hannes, Do¨rfler, Arnd, Schwab, Stefan, and Huttner, Hagen B
- Abstract
ObjectiveTo determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH.MethodsRetrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC.ResultsIHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04–1.93) vs non-LDSH: 1.32 (0.33–3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38–4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4–6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04–0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11–0.78); p=0.014) were significantly associated with fewer IHC.ConclusionsHeparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.
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- 2019
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37. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis
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Verde, Federico, Steinacker, Petra, Weishaupt, Jochen H, Kassubek, Jan, Oeckl, Patrick, Halbgebauer, Steffen, Tumani, Hayrettin, von Arnim, Christine A F, Dorst, Johannes, Feneberg, Emily, Mayer, Benjamin, Mu¨ller, Hans-Peter, Gorges, Martin, Rosenbohm, Angela, Volk, Alexander E, Silani, Vincenzo, Ludolph, Albert C, and Otto, Markus
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ObjectiveTo determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS).MethodsThis single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer’s disease, 19 with Parkinson’s disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology.ResultsSerum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time.ConclusionsSerum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.
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- 2019
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38. Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase
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Oeckl, Patrick, Weydt, Patrick, Steinacker, Petra, Anderl-Straub, Sarah, Nordin, Frida, Volk, Alexander E, Diehl-Schmid, Janine, Andersen, Peter M, Kornhuber, Johannes, Danek, Adrian, Fassbender, Klaus, Fliessbach, Klaus, Jahn, Holger, Lauer, Martin, Mu¨ller, Kathrin, Knehr, Antje, Prudlo, Johannes, Schneider, Anja, Thal, Dietmar R, Yilmazer-Hanke, Deniz, Weishaupt, Jochen H, Ludolph, Albert C, and Otto, Markus
- Abstract
ObjectiveTo investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers.MethodsThe neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA.ResultsCSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (−80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05).ConclusionOur data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.
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- 2019
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39. Symptomatic pharmacotherapy in ALS: data analysis from a platform-based medication management programme
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Meyer, Thomas, Kettemann, Dagmar, Maier, André, Grehl, Torsten, Weyen, Ute, Grosskreutz, Julian, Steinbach, Robert, Norden, Jenny, George, Annette, Hermann, Andreas, Guenther, René, Petri, Susanne, Schreiber-Katz, Olivia, Dorst, Johannes, Ludolph, Albert C, Walter, Bertram, Mu¨nch, Christoph, and Spittel, Susanne
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- 2020
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40. Serum neurofilament light chain in behavioral variant frontotemporal dementia
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Steinacker, Petra, Anderl-Straub, Sarah, Diehl-Schmid, Janine, Semler, Elisa, Uttner, Ingo, von Arnim, Christine A.F., Barthel, Henryk, Danek, Adrian, Fassbender, Klaus, Fliessbach, Klaus, Foerstl, Hans, Grimmer, Timo, Huppertz, Hans-Jürgen, Jahn, Holger, Kassubek, Jan, Kornhuber, Johannes, Landwehrmeyer, Bernhard, Lauer, Martin, Maler, Juan Manuel, Mayer, Benjamin, Oeckl, Patrick, Prudlo, Johannes, Schneider, Anja, Volk, Alexander E., Wiltfang, Jens, Schroeter, Matthias L., Ludolph, Albert C., and Otto, Markus
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- 2018
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41. Association of Serum Retinol-Binding Protein 4 Concentration With Risk for and Prognosis of Amyotrophic Lateral Sclerosis
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Rosenbohm, Angela, Nagel, Gabriele, Peter, Raphael S., Brehme, Torben, Koenig, Wolfgang, Dupuis, Luc, Rothenbacher, Dietrich, and Ludolph, Albert C.
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IMPORTANCE: Knowledge about the metabolic states of patients with amyotrophic lateral sclerosis (ALS) may provide a therapeutic approach. OBJECTIVE: To investigate the association between the onset and prognosis of ALS and serum retinol-binding protein 4 (RBP4) concentration as a biomarker for insulin resistance and vitamin A metabolism. DESIGN, SETTING, AND PARTICIPANTS: Case-control design for risk factors of ALS; cohort design for prognostic factors within ALS cases. Between October 1, 2010, and June 30, 2014, a population-based case-control study with randomly selected controls was established based on the ALS Registry Swabia in southern Germany, with a target population of 8.4 million inhabitants. Response rates were 64.8% among the cases and 18.7% among the controls. The dates of analysis were April 2016 to May 2017. MAIN OUTCOMES AND MEASURES: Serum samples were measured for RBP4. Information on covariates was assessed by an interview-based standardized questionnaire. Main outcomes and measures were adjusted odds ratios for risk of ALS associated with serum RBP4 concentration, as well as time to death associated with RBP4 concentration at baseline in ALS cases only. Conditional logistic regression was applied to calculate multivariable odds ratios for risk of ALS. Survival models were used in cases only to appraise their prognostic value. RESULTS: Data from 289 patients with ALS (mean [SD] age, 65.7 [10.5] years; 172 [59.5%] male) and 504 controls (mean [SD] age, 66.3 [9.8] years; 299 [59.3%] male) were included in the case-control study. Compared with controls, ALS cases were characterized by lower body mass index, less educational attainment, smoking, light occupational work intensity, and self-reported diabetes. The median serum RBP4 concentration was lower in ALS cases than in controls (54.0 vs 59.5 mg/L). In the multivariable model, increasing RBP4 concentration was associated with reduced odds for ALS (top vs bottom quartile odds ratio, 0.36; 95% CI, 0.22-0.59; P for trend <.001), which persisted after further adjustment for renal function and for leptin and adiponectin. Among 279 ALS cases during a median follow-up of 14.5 months, 104 died (mean [SD] age, 68.9 [10.3] years; 56 [53.9%] male). In this ALS cohort, an inverse association was found between serum RBP4 concentration as a continuous measure and survival. CONCLUSIONS AND RELEVANCE: RBP4 was inversely related to risk for and prognosis of ALS, suggesting that vitamin A metabolism or impaired insulin signaling could be involved. Further research, including a prospective design and other biological markers, is necessary to clarify the role of insulin resistance in the pathogenesis of ALS.
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- 2018
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42. Cognitive phenotypes of sequential staging in amyotrophic lateral sclerosis
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Lulé, Dorothée, Böhm, Sarah, Müller, Hans-Peter, Aho-Özhan, Helena, Keller, Jürgen, Gorges, Martin, Loose, Markus, Weishaupt, Jochen H., Uttner, Ingo, Pinkhardt, Elmar, Kassubek, Jan, Del Tredici, Kelly, Braak, Heiko, Abrahams, Sharon, and Ludolph, Albert C.
- Abstract
Sequential spread of TDP-43 load in the brain may be a pathological characteristic of amyotrophic lateral sclerosis (ALS). Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) based marker of this pathological feature. Cognitive deficits known to be present in a subset of ALS patients might act as an additional in vivo clinical marker of disease spread.
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- 2018
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43. Imaging the pathoanatomy of amyotrophic lateral sclerosis in vivo: targeting a propagation-based biological marker
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Kassubek, Jan, Muller, Hans-Peter, Del Tredici, Kelly, Luléé, Dorothée, Gorges, Martin, Braak, Heiko, and Ludolph, Albert C
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ObjectiveNeuropathological studies in amyotrophic lateral sclerosis (ALS) have shown a dissemination in a regional sequence in four anatomically defined patterns. The aim of this retrospective study was to see whether longitudinal diffusion tensor imaging (DTI) data support the pathological findings.MethodsThe application of DTI analysis to fibre structures that are prone to be involved at each neuropathological pattern of ALS was performed in a monocentre sample of 67 patients with ALS and 31 controls that obtained at least one follow-up scan after a median of 6 months.ResultsAt the group level, longitudinal ALS data showed significant differences for the stage-related tract systems. At the individual level, 27% of the longitudinally scanned patients with ALS showed an increase in ALS stage, while the remaining were stable or were at the highest ALS stage. Longitudinal fractional anisotropy changes in the respective tract systems correlated significantly with the slope of the revised ALS functional rating scale.InterpretationThe DTI-based protocol was able to image the disease patterns of ALS in vivo cross-sectionally and longitudinally, in support of DTI as a technical marker to image ALS stages.
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- 2018
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44. Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis
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Feneberg, Emily, Oeckl, Patrick, Steinacker, Petra, Verde, Federico, Barro, Christian, Van Damme, Philip, Gray, Elizabeth, Grosskreutz, Julian, Jardel, Claude, Kuhle, Jens, Koerner, Sonja, Lamari, Foudil, Amador, Maria del Mar, Mayer, Benjamin, Morelli, Claudia, Muckova, Petra, Petri, Susanne, Poesen, Koen, Raaphorst, Joost, Salachas, François, Silani, Vincenzo, Stubendorff, Beatrice, Turner, Martin R., Verbeek, Marcel M., Weishaupt, Jochen H., Weydt, Patrick, Ludolph, Albert C., and Otto, Markus
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- 2018
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45. Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression
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Steinacker, Petra, Verde, Federico, Fang, Lubin, Feneberg, Emily, Oeckl, Patrick, Roeber, Sigrun, Anderl-Straub, Sarah, Danek, Adrian, Diehl-Schmid, Janine, Fassbender, Klaus, Fliessbach, Klaus, Foerstl, Hans, Giese, Armin, Jahn, Holger, Kassubek, Jan, Kornhuber, Johannes, Landwehrmeyer, G Bernhard, Lauer, Martin, Pinkhardt, Elmar Hans, Prudlo, Johannes, Rosenbohm, Angela, Schneider, Anja, Schroeter, Matthias L, Tumani, Hayrettin, von Arnim, Christine A F, Weishaupt, Jochen, Weydt, Patrick, Ludolph, Albert C, Yilmazer Hanke, Deniz, and Otto, Markus
- Abstract
ObjectivesNeurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1).MethodsAltogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression.ResultsIn ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68).ConclusionsCHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.
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- 2018
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46. Comprehensive analysis of the mutation spectrum in 301 German ALS families
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Muller, Kathrin, Brenner, David, Weydt, Patrick, Meyer, Thomas, Grehl, Torsten, Petri, Susanne, Grosskreutz, Julian, Schuster, Joachim, Volk, Alexander E, Borck, Guntram, Kubisch, Christian, Klopstock, Thomas, Zeller, Daniel, Jablonka, Sibylle, Sendtner, Michael, Klebe, Stephan, Knehr, Antje, Gunther, Kornelia, Weis, Joachim, Claeys, Kristl G, Schrank, Berthold, Sperfeld, Anne-Dorte, Hubers, Annemarie, Otto, Markus, Dorst, Johannes, Meitinger, Thomas, Strom, Tim M, Andersen, Peter M, Ludolph, Albert C, and Weishaupt, Jochen H
- Abstract
ObjectivesRecent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.MethodsHere we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBPor TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.ConclusionsWe here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
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- 2018
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47. Editorial: Amyotrophic lateral sclerosis
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Ludolph, Albert C.
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- 2022
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48. Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias
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Steinacker, Petra, Semler, Elisa, Anderl-Straub, Sarah, Diehl-Schmid, Janine, Schroeter, Matthias L., Uttner, Ingo, Foerstl, Hans, Landwehrmeyer, Bernhard, von Arnim, Christine A.F., Kassubek, Jan, Oeckl, Patrick, Huppertz, Hans-Jürgen, Fassbender, Klaus, Fliessbach, Klaus, Prudlo, Johannes, Roßmeier, Carola, Kornhuber, Johannes, Schneider, Anja, Volk, Alexander E., Lauer, Martin, Danek, Adrian, Ludolph, Albert C., and Otto, Markus
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- 2017
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49. Cortical influences drive amyotrophic lateral sclerosis
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Eisen, Andrew, Braak, Heiko, Del Tredici, Kelly, Lemon, Roger, Ludolph, Albert C, and Kiernan, Matthew C
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The early motor manifestations of sporadic amyotrophic lateral sclerosis (ALS), while rarely documented, reflect failure of adaptive complex motor skills. The development of these skills correlates with progressive evolution of a direct corticomotoneuronal system that is unique to primates and markedly enhanced in humans. The failure of this system in ALS may translate into the split hand presentation, gait disturbance, split leg syndrome and bulbar symptomatology related to vocalisation and breathing, and possibly diffuse fasciculation, characteristic of ALS. Clinical neurophysiology of the brain employing transcranial magnetic stimulation has convincingly demonstrated a presymptomatic reduction or absence of short interval intracortical inhibition, accompanied by increased intracortical facilitation, indicating cortical hyperexcitability. The hallmark of the TDP-43 pathological signature of sporadic ALS is restricted to cortical areas as well as to subcortical nuclei that are under the direct control of corticofugal projections. This provides anatomical support that the origins of the TDP-43 pathology reside in the cerebral cortex itself, secondarily in corticofugal fibres and the subcortical targets with which they make monosynaptic connections. The latter feature explains the multisystem degeneration that characterises ALS. Consideration of ALS as a primary neurodegenerative disorder of the human brain may incorporate concepts of prion-like spread at synaptic terminals of corticofugal axons. Further, such a concept could explain the recognised widespread imaging abnormalities of the ALS neocortex and the accepted relationship between ALS and frontotemporal dementia.
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- 2017
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50. Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
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Freischmidt, Axel, Müller, Kathrin, Ludolph, Albert C., Weishaupt, Jochen H., and Andersen, Peter M.
- Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.
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- 2017
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