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1. Tau deposition patterns are associated with functional connectivity in primary tauopathies

Author

Franzmeier, N, Brendel, M, Beyer, L, Slemann, L, Kovacs, GG, Arzberger, T, Kurz, C, Respondek, G, Lukic, MJ, Biel, D, Rubinski, A, Frontzkowski, L, Hummel, S, Muller, A, Finze, A, Palleis, C, Joseph, E, Weidinger, E, Katzdobler, S, Song, M, Biechele, G, Kern, M, Scheifele, M, Rauchmann, B-S, Perneczky, R, Rullman, M, Patt, M, Schildan, A, Barthel, H, Sabri, O, Rumpf, JJ, Schroeter, ML, Classen, J, Villemagne, V, Seibyl, J, Stephens, AW, Lee, EB, Coughlin, DG, Giese, A, Grossman, M, McMillan, CT, Gelpi, E, Molina-Porcel, L, Compta, Y, van Swieten, JC, Laat, LD, Troakes, C, Al-Sarraj, S, Robinson, JL, Xie, SX, Irwin, DJ, Roeber, S, Herms, J, Simons, M, Bartenstein, P, Lee, VM, Trojanowski, JQ, Levin, J, Hoeglinger, G, Ewers, M, Franzmeier, N, Brendel, M, Beyer, L, Slemann, L, Kovacs, GG, Arzberger, T, Kurz, C, Respondek, G, Lukic, MJ, Biel, D, Rubinski, A, Frontzkowski, L, Hummel, S, Muller, A, Finze, A, Palleis, C, Joseph, E, Weidinger, E, Katzdobler, S, Song, M, Biechele, G, Kern, M, Scheifele, M, Rauchmann, B-S, Perneczky, R, Rullman, M, Patt, M, Schildan, A, Barthel, H, Sabri, O, Rumpf, JJ, Schroeter, ML, Classen, J, Villemagne, V, Seibyl, J, Stephens, AW, Lee, EB, Coughlin, DG, Giese, A, Grossman, M, McMillan, CT, Gelpi, E, Molina-Porcel, L, Compta, Y, van Swieten, JC, Laat, LD, Troakes, C, Al-Sarraj, S, Robinson, JL, Xie, SX, Irwin, DJ, Roeber, S, Herms, J, Simons, M, Bartenstein, P, Lee, VM, Trojanowski, JQ, Levin, J, Hoeglinger, G, and Ewers, M

Abstract

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

Published
2022

3. Binding characteristics of [18F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET

Author

Song, M, Beyer, L, Kaiser, L, Barthel, H, van Eimeren, T, Marek, K, Nitschmann, A, Scheifele, M, Palleis, C, Respondek, G, Kern, M, Biechele, G, Hammes, J, Bischof, G, Barbe, M, Onur, O, Jessen, F, Saur, D, Schroeter, ML, Rumpf, J-J, Rullmann, M, Schildan, A, Patt, M, Neumaier, B, Barret, O, Madonia, J, Russell, DS, Stephens, AW, Mueller, A, Roeber, S, Herms, J, Botzel, K, Danek, A, Levin, J, Classen, J, Hoglinger, GU, Bartenstein, P, Villemagne, V, Drzezga, A, Seibyl, J, Sabri, O, Boening, G, Ziegler, S, Brendel, M, Song, M, Beyer, L, Kaiser, L, Barthel, H, van Eimeren, T, Marek, K, Nitschmann, A, Scheifele, M, Palleis, C, Respondek, G, Kern, M, Biechele, G, Hammes, J, Bischof, G, Barbe, M, Onur, O, Jessen, F, Saur, D, Schroeter, ML, Rumpf, J-J, Rullmann, M, Schildan, A, Patt, M, Neumaier, B, Barret, O, Madonia, J, Russell, DS, Stephens, AW, Mueller, A, Roeber, S, Herms, J, Botzel, K, Danek, A, Levin, J, Classen, J, Hoglinger, GU, Bartenstein, P, Villemagne, V, Drzezga, A, Seibyl, J, Sabri, O, Boening, G, Ziegler, S, and Brendel, M

Abstract

The novel tau-PET tracer [18F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer's disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [18F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [18F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [18F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [18F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.

Published
2021

9. Clinical Conditions 'Suggestive of Progressive Supranuclear Palsy'—Diagnostic Performance

Author

Grimm, M.-J. Respondek, G. Stamelou, M. Arzberger, T. Ferguson, L. Gelpi, E. Giese, A. Grossman, M. Irwin, D.J. Pantelyat, A. Rajput, A. Roeber, S. van Swieten, J.C. Troakes, C. Meissner, W.G. Nilsson, C. Piot, I. Compta, Y. Rowe, J.B. Höglinger, G.U. for the Movement Disorder Society-Endorsed PSP Study Group

Subjects
mental disorders, behavioral disciplines and activities, eye diseases, nervous system diseases
Abstract

Background: The Movement Disorder Society diagnostic criteria for progressive supranuclear palsy introduced the diagnostic certainty level “suggestive of progressive supranuclear palsy” for clinical conditions with subtle signs, suggestive of the disease. This category aims at the early identification of patients, in whom the diagnosis may be confirmed as the disease evolves. Objective: To assess the diagnostic performance of the defined clinical conditions suggestive of progressive supranuclear palsy in an autopsy-confirmed cohort. Methods: Diagnostic performance of the criteria was analyzed based on retrospective clinical data of 204 autopsy-confirmed patients with progressive supranuclear palsy and 216 patients with other neurological diseases. Results: The conditions suggestive of progressive supranuclear palsy strongly increased the sensitivity compared to the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria. Within the first year after symptom onset, 40% of patients with definite progressive supranuclear palsy fulfilled criteria for suggestive of progressive supranuclear palsy. Two-thirds of patients suggestive of progressive supranuclear palsy evolved into probable progressive supranuclear palsy after an average of 3.6 years. Application of the criteria for suggestive of progressive supranuclear palsy reduced the average time to diagnosis from 3.8 to 2.2 years. Conclusions: Clinical conditions suggestive of progressive supranuclear palsy allow earlier identification of patients likely to evolve into clinically possible or probable progressive supranuclear and to have underlying progressive supranuclear palsy pathology. Further work needs to establish the specificity and positive predictive value of this category in real-life clinical settings, and to develop specific biomarkers that enhance their diagnostic accuracy in early disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Published
2020

10. Clinical Conditions “Suggestive of Progressive Supranuclear Palsy”—Diagnostic Performance

Author

Grimm, M.-J. (Max-Joseph), Respondek, G. (Gesine), Stamelou, M. (Maria), Arzberger, T. (T.), Ferguson, L.W. (Leslie W.), Gelpi, E. (Ellen), Giese, A. (Armin), Grossman, M. (Murray), Irwin, D.J. (David J.), Pantelyat, A. (Alexander), Rajput, A. (Alex), Roeber, S. (Sigrun), Swieten, J.C. (John) van, Troakes, C. (Claire), Meissner, W.G. (Wassilios G.), Nilsson, C. (Christer), Piot, I. (Ines), Compta, Y. (Yaroslau), Rowe, J.B. (James), Hoglinger, G. (Gunter), Grimm, M.-J. (Max-Joseph), Respondek, G. (Gesine), Stamelou, M. (Maria), Arzberger, T. (T.), Ferguson, L.W. (Leslie W.), Gelpi, E. (Ellen), Giese, A. (Armin), Grossman, M. (Murray), Irwin, D.J. (David J.), Pantelyat, A. (Alexander), Rajput, A. (Alex), Roeber, S. (Sigrun), Swieten, J.C. (John) van, Troakes, C. (Claire), Meissner, W.G. (Wassilios G.), Nilsson, C. (Christer), Piot, I. (Ines), Compta, Y. (Yaroslau), Rowe, J.B. (James), and Hoglinger, G. (Gunter)

Abstract

Background: The Movement Disorder Society diagnostic criteria for progressive supranuclear palsy introduced the diagnostic certainty level “suggestive of progressive supranuclear palsy” for clinical conditions with subtle signs, suggestive of the disease. This category aims at the early identification of patients, in whom the diagnosis may be confirmed as the disease evolves. Objective: To assess the diagnostic performance of the defined clinical conditions suggestive of progressive supranuclear palsy in an autopsy-confirmed cohort. Methods: Diagnostic performance of the criteria was analyzed based on retrospective clinical data of 204 autopsy-confirmed patients with progressive supranuclear palsy and 216 patients with other neurological diseases. Results: The conditions suggestive of progressive supranuclear palsy strongly increased the sensitivity compared to the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria. Within the first year after symptom onset, 40% of patients with definite progressive supranuclear palsy fulfilled criteria for suggestive of progressive supranuclear palsy. Two-thirds of patients suggestive of progressive supranuclear palsy evolved into probable progressive supranuclear palsy after an average of 3.6 years. Application of the criteria for suggestive of progressive supranuclear palsy reduced the average time to diagnosis from 3.8 to 2.2 years. Conclusions: Clinical conditions suggestive of progressive supranuclear palsy allow earlier identification of patients likely to evolve into clinically possible or probable progressive supranuclear and to have underlying progressive supranuclear palsy pathology. Further work needs to establish the specificity and positive predictive value of this category in real-life clinical settings, and to develop specific biomarkers that enhance their diagnostic accuracy in early disease stages.

Published
2020
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11. Distribution patterns of tau pathology in progressive supranuclear palsy

Author

Kovacs, G.G. (Gabor), Lukic, M.J. (Milica Jecmenica), Irwin, D.J. (David J.), Arzberger, T. (T.), Respondek, G. (Gesine), Lee, E.B. (Edward B.), Coughlin, D. (David), Giese, A. (Armin), Grossman, M. (Murray), Kurz, C. (Carolin), McMillan, C.T. (Corey T.), Gelpi, E. (Ellen), Compta, Y. (Yaroslau), Swieten, J.C. (John) van, Laat, L.D. (Laura Donker), Troakes, C. (Claire), Al-Sarraj, S. (Safa), Robinson, J.L. (John L.), Roeber, S. (Sigrun), Xie, S.X. (Sharon X.), Lee, V.M.Y. (Virginia), Trojanowski, J.Q. (John Q.), Hoglinger, G. (Gunter), Kovacs, G.G. (Gabor), Lukic, M.J. (Milica Jecmenica), Irwin, D.J. (David J.), Arzberger, T. (T.), Respondek, G. (Gesine), Lee, E.B. (Edward B.), Coughlin, D. (David), Giese, A. (Armin), Grossman, M. (Murray), Kurz, C. (Carolin), McMillan, C.T. (Corey T.), Gelpi, E. (Ellen), Compta, Y. (Yaroslau), Swieten, J.C. (John) van, Laat, L.D. (Laura Donker), Troakes, C. (Claire), Al-Sarraj, S. (Safa), Robinson, J.L. (John L.), Roeber, S. (Sigrun), Xie, S.X. (Sharon X.), Lee, V.M.Y. (Virginia), Trojanowski, J.Q. (John Q.), and Hoglinger, G. (Gunter)

Abstract

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We

Published
2020
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12. [18F]PI-2620 Tau PET to Improve Imaging-Based Diagnosis of PSP

Author

Messerschmidt, K., Barthel, H., Brendel, M., Van Eimeren, T., Marek, K., Villemagne, V., Rumpf, J., Saur, D., Schroeter, M., Rullmann, M., Hoffmann, K., Scherlach, C., Rauchmann, B., Schildan, A., Patt, M., Beyer, L., Song, M., Palleis, C., Gehmeyr, M., Fietzek, U., Respondek, G., Sauerbeck, J., Nitschmann, A., Zach, C., Hammes, J., Barbe, M., Onur, O., Jessen, F., Neumaier, B., Barret, O., Madonia, J., Russell, D., Stephens, A., Roeber, S., Herms, J., Boetzel, K., Bartenstein, P., Levin, J., Drzezga, A., Seibyl, J., Hoeglinger, G., Classen, J., Sabri, O., Messerschmidt, K., Barthel, H., Brendel, M., Van Eimeren, T., Marek, K., Villemagne, V., Rumpf, J., Saur, D., Schroeter, M., Rullmann, M., Hoffmann, K., Scherlach, C., Rauchmann, B., Schildan, A., Patt, M., Beyer, L., Song, M., Palleis, C., Gehmeyr, M., Fietzek, U., Respondek, G., Sauerbeck, J., Nitschmann, A., Zach, C., Hammes, J., Barbe, M., Onur, O., Jessen, F., Neumaier, B., Barret, O., Madonia, J., Russell, D., Stephens, A., Roeber, S., Herms, J., Boetzel, K., Bartenstein, P., Levin, J., Drzezga, A., Seibyl, J., Hoeglinger, G., Classen, J., and Sabri, O.

Published
2020

13. Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy

Author

Brendel, M, Barthel, H, van Eimeren, T, Marek, K, Beyer, L, Song, M, Palleis, C, Gehmeyr, M, Fietzek, U, Respondek, G, Sauerbeck, J, Nitschmann, A, Zach, C, Hammes, J, Barbe, MT, Onur, O, Jessen, F, Saur, D, Schroeter, ML, Rumpf, J-J, Rullmann, M, Schildan, A, Patt, M, Neumaier, B, Barret, O, Madonia, J, Russell, DS, Stephens, A, Roeber, S, Herms, J, Boetzel, K, Classen, J, Bartenstein, P, Villemagne, V, Levin, J, Hoeglinger, GU, Drzezga, A, Seibyl, J, Sabri, O, Brendel, M, Barthel, H, van Eimeren, T, Marek, K, Beyer, L, Song, M, Palleis, C, Gehmeyr, M, Fietzek, U, Respondek, G, Sauerbeck, J, Nitschmann, A, Zach, C, Hammes, J, Barbe, MT, Onur, O, Jessen, F, Saur, D, Schroeter, ML, Rumpf, J-J, Rullmann, M, Schildan, A, Patt, M, Neumaier, B, Barret, O, Madonia, J, Russell, DS, Stephens, A, Roeber, S, Herms, J, Boetzel, K, Classen, J, Bartenstein, P, Villemagne, V, Levin, J, Hoeglinger, GU, Drzezga, A, Seibyl, J, and Sabri, O

Abstract

IMPORTANCE: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. OBJECTIVE: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. MAIN OUTCOMES AND MEASURES: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. RESULTS: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10

Published
2020

14. Distribution patterns of tau pathology in progressive supranuclear palsy

Author

Kovacs, GG, Lukic, MJ, Irwin, DJ, Arzberger, T, Respondek, G, Lee, EB, Coughlin, D, Giese, A, Grossman, M, Kurz, C, McMillan, CT, Gelpi, E, Compta, Y, van Swieten, J.C., Donker Kaat, Laura, Troakes, C, Al-Sarraj, S, Robinson, JL, Roeber, S, Xie, SX, Lee, VMY, Trojanowski, JQ, Höglinger, GU, Kovacs, GG, Lukic, MJ, Irwin, DJ, Arzberger, T, Respondek, G, Lee, EB, Coughlin, D, Giese, A, Grossman, M, Kurz, C, McMillan, CT, Gelpi, E, Compta, Y, van Swieten, J.C., Donker Kaat, Laura, Troakes, C, Al-Sarraj, S, Robinson, JL, Roeber, S, Xie, SX, Lee, VMY, Trojanowski, JQ, and Höglinger, GU

Published
2020

15. Clinical Conditions “Suggestive of Progressive Supranuclear Palsy”—Diagnostic Performance

Author

Grimm, MJ, Respondek, G, Stamelou, M, Arzberger, T, Ferguson, L, Gelpi, E, Giese, A, Grossman, M, Irwin, DJ, Pantelyat, A, Rajput, A, Roeber, S, van Swieten, J.C., Troakes, C, Meissner, WG, Nilsson, C, Piot, I, Compta, Y, Rowe, JB, Höglinger, GU, Grimm, MJ, Respondek, G, Stamelou, M, Arzberger, T, Ferguson, L, Gelpi, E, Giese, A, Grossman, M, Irwin, DJ, Pantelyat, A, Rajput, A, Roeber, S, van Swieten, J.C., Troakes, C, Meissner, WG, Nilsson, C, Piot, I, Compta, Y, Rowe, JB, and Höglinger, GU

Published
2020

17. How to apply the movement disorder society criteria for diagnosis of progressive supranuclear palsy

Author

Grimm, M.-J. Respondek, G. Stamelou, M. Arzberger, T. Ferguson, L. Gelpi, E. Giese, A. Grossman, M. Irwin, D.J. Pantelyat, A. Rajput, A. Roeber, S. van Swieten, J.C. Troakes, C. Antonini, A. Bhatia, K.P. Colosimo, C. van Eimeren, T. Kassubek, J. Levin, J. Meissner, W.G. Nilsson, C. Oertel, W.H. Piot, I. Poewe, W. Wenning, G.K. Boxer, A. Golbe, L.I. Josephs, K.A. Litvan, I. Morris, H.R. Whitwell, J.L. Compta, Y. Corvol, J.-C. Lang, A.E. Rowe, J.B. Höglinger, G.U. for the Movement Disorder Society-endorsed PSP Study Group

Abstract

Background: The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them. Methods: We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations. Results: Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1. Conclusions: The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society. © 2019 International Parkinson and Movement Disorder Society

Published
2019

19. [A Pair of Siblings with a rare R5H-Mutation in Exon 1 of the MAPT-Gene]

Author

Henz, S., Ackl, N., Knels, C., Rominger, A., Flatz, W., Teipel, S., Huppertz, H. J., Roeber, S., Neumann, Manuela, and Danek, A.

Subjects
Male, genetics [Mutation], MAPT protein, human, tau Proteins, genetics [Psychotic Disorders], Magnetic Resonance Imaging, genetics [tau Proteins], Aphasia, Primary Progressive, ddc:150, Psychotic Disorders, Frontotemporal Dementia, Positron-Emission Tomography, Mutation, Disease Progression, Humans, psychology [Aphasia, Primary Progressive], Female, Age of Onset, diagnosis [Aphasia, Primary Progressive], genetics [Frontotemporal Dementia], genetics [Aphasia, Primary Progressive], Aged
Abstract

We report on a female patient presenting with primary progressive aphasia (PPA) and her brother presenting with psychosis. Both siblings had an R5H-mutation in exon 1 of the MAPT-gene. The PPA patient presented for the first time at the age of 72 years with a 4-year-history of language impairment. After a progressive course the patient died at the age of 76 years. The R5H-MAPT-gene mutation detected in the siblings has been described only once in 2002 by Hayashi et al. [1]. In this previous case from Japan, a 75-year-old patient initially displayed amnesia and disorientation. He became bedridden, with progressive mutism and rigidity of the upper extremities. Noteworthy are the manifold signs and symptoms in R5H-mutations and the late age of onset. For future trials, the detection of biomarkers for frontotemporal lobar degeneration in presymptomatic cohorts like the genetic frontotemporal dementia initiative (GENFI) is of help for stratifying subjects at risk.

Published
2015
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21. White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Author

Craggs, LJL, Yamamoto, Y, Ihara, M, Fenwick, R, Burke, M, Oakley, AE, Roeber, S, Duering, M, Kretzschmar, H, and Kalaria, RN

Abstract

Background; Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM. Methods; We used post‐mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro‐caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles. Results; The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P

Published
2014

22. The Phenotypic Spectrum of Progressive Supranuclear Palsy: A Retrospective Multicenter Study of 100 Definite Cases

Author

Respondek, G, Stamelou, M, Kurz, C, Ferguson, LW, Rajput, A, Chiu, Wang Zheng, van Swieten, J.C., Troakes, C, al Sarraj, S, Gelpi, E, Gaig, C, Tolosa, E, Oertel, WH, Giese, A, Roeber, S, Arzberger, T, Wagenpfeil, S, Hoglinger, GU, and Neurology

Abstract

The phenotypic variability of progressive supranuclear palsy (PSP) may account for its frequent misdiagnosis, in particular in early stages of the disease. However, large multicenter studies to define the frequency and natural history of PSP phenotypes are missing. In a cohort of 100 auto-psyconfirmed patients we studied the phenotypic spectrum of PSP by retrospective chart review. Patients were derived from five brain banks with expertise in neurodegenerative disorders with referrals from multiple academic hospitals. The clinical characteristics of the 100 cases showed remarkable heterogeneity. Most strikingly, only 24% of cases presented as Richardson's Syndrome (RS), and more than half of the cases either showed overlapping features of several predescribed phenotypes, or features not fitting proposed classification criteria for PSP phenotypes. Classification of patients according to predominant clinical features in the first 2 years of the disease course allowed a more comprehensive description of the phenotypic spectrum. These predominance types differed significantly with regard to survival time and frequency of cognitive deficits. In summary, the phenotypic spectrum of PSP may be broader and more variable than previously described in single-center studies. Thus, too strict clinical criteria defining distinct phenotypes may not reflect this variability. A more pragmatic clinical approach using predominance types could potentially be more helpful in the early recognition of and for making prognostic predictions for these patients. Given the limitations arising from the retrospective nature of this analysis, a systematic validation in a prospective cohort study is imperative. (C) 2014 International Parkinson and Movement Disorder Society

Published
2014

23. The phenotypic spectrum of progressive supranuclear palsy: A retrospective multicenter study of 100 definite cases

Author

Respondek, G. Stamelou, M. Kurz, C. Ferguson, L.W. Rajput, A. Chiu, W.Z. van Swieten, J.C. Troakes, C. al Sarraj, S. Gelpi, E. Gaig, C. Tolosa, E. Oertel, W.H. Giese, A. Roeber, S. Arzberger, T. Wagenpfeil, S. Höglinger, G.U.

Abstract

The phenotypic variability of progressive supranuclear palsy (PSP) may account for its frequent misdiagnosis, in particular in early stages of the disease. However, large multicenter studies to define the frequency and natural history of PSP phenotypes are missing. In a cohort of 100 autopsy-confirmed patients we studied the phenotypic spectrum of PSP by retrospective chart review. Patients were derived from five brain banks with expertise in neurodegenerative disorders with referrals from multiple academic hospitals. The clinical characteristics of the 100 cases showed remarkable heterogeneity. Most strikingly, only 24% of cases presented as Richardson's Syndrome (RS), and more than half of the cases either showed overlapping features of several predescribed phenotypes, or features not fitting proposed classification criteria for PSP phenotypes. Classification of patients according to predominant clinical features in the first 2 years of the disease course allowed a more comprehensive description of the phenotypic spectrum. These predominance types differed significantly with regard to survival time and frequency of cognitive deficits. In summary, the phenotypic spectrum of PSP may be broader and more variable than previously described in single-center studies. Thus, too strict clinical criteria defining distinct phenotypes may not reflect this variability. A more pragmatic clinical approach using predominance types could potentially be more helpful in the early recognition of and for making prognostic predictions for these patients. Given the limitations arising from the retrospective nature of this analysis, a systematic validation in a prospective cohort study is imperative. © 2014 International Parkinson and Movement Disorder Society.

Published
2014

24. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

Author

Kouri, N, Ross, OA, Dombroski, B, Younkin, CS, Serie, DJ, Soto-Ortolaza, A, Baker, M, Finch, NCA, Yoon, H, Kim, J, Fujioka, S, McLean, CA, Ghetti, B, Spina, S, Cantwell, LB, Farlow, MR, Grafman, J, Huey, ED, Han, MR, Beecher, S, Geller, ET, Kretzschmar, HA, Roeber, S, Gearing, M, Juncos, JL, Vonsattel, JPG, Van Deerlin, VM, Grossman, M, Hurtig, HI, Gross, RG, Arnold, SE, Trojanowski, JQ, Lee, VM, Wenning, GK, White, CL, Hoeglinger, GU, Mueller, U, Devlin, B, Golbe, LI, Crook, J, Parisi, JE, Boeve, BF, Josephs, KA, Wszolek, ZK, Uitti, RJ, Graff-Radford, NR, Litvan, I, Younkin, SG, Wang, L-S, Ertekin-Taner, N, Rademakers, R, Hakonarsen, H, Schellenberg, GD, Dickson, DW, Kouri, N, Ross, OA, Dombroski, B, Younkin, CS, Serie, DJ, Soto-Ortolaza, A, Baker, M, Finch, NCA, Yoon, H, Kim, J, Fujioka, S, McLean, CA, Ghetti, B, Spina, S, Cantwell, LB, Farlow, MR, Grafman, J, Huey, ED, Han, MR, Beecher, S, Geller, ET, Kretzschmar, HA, Roeber, S, Gearing, M, Juncos, JL, Vonsattel, JPG, Van Deerlin, VM, Grossman, M, Hurtig, HI, Gross, RG, Arnold, SE, Trojanowski, JQ, Lee, VM, Wenning, GK, White, CL, Hoeglinger, GU, Mueller, U, Devlin, B, Golbe, LI, Crook, J, Parisi, JE, Boeve, BF, Josephs, KA, Wszolek, ZK, Uitti, RJ, Graff-Radford, NR, Litvan, I, Younkin, SG, Wang, L-S, Ertekin-Taner, N, Rademakers, R, Hakonarsen, H, Schellenberg, GD, and Dickson, DW

Abstract

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).

Published
2015

25. Distinct pathological subtypes of FTLD-FUS

Author

Mackenzie, I R A, Munoz, D G, Kusaka, H, Yokota, O, Ishihara, K, Roeber, S, Kretzschmar, H A, Cairns, N J, Neumann, M, and University of Zurich

Subjects
2734 Pathology and Forensic Medicine, 2728 Neurology (clinical), 10208 Institute of Neuropathology, 2804 Cellular and Molecular Neuroscience, 570 Life sciences, biology, 610 Medicine & health
Published
2011

27. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Author

Hoglinger, G. (Gunter), Melhem, N.M. (Nadine), Dickson, D. (Dennis), Sleiman, P.M.A. (Patrick), Wang, L.S. (Li-San), Klei, L. (Lambertus), Rademakers, R. (Rosa), Silva, R. (Rohan) de, Litvan, I. (Irene), Riley, D.E. (David), Swieten, J.C. (John) van, Heutink, P. (Peter), Wszolek, Z.K. (Zbigniew), Uitti, R.J. (Ryan), Vandrovcova, J. (Jana), Hurtig, H.I. (Howard), Gross, R.G. (Rachel), Maetzler, W. (Walter), Goldwurm, S. (Stefano), Tolosa, E., Borroni, B. (Barbara), Pastor, P. (Pau), Cantwell, L.B. (Laura), Han, M.R., Dillman, A. (Allissa), Brug, M.P. (Marcel) van der, Gibbs, J. (Raphael), Cookson, M.R. (Mark), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Farrer, M.J. (Matthew), Yu, C.-E. (Changen), Golbe, L.I. (Lawrence), Revesz, T. (Tamas), Hardy, J. (John), Lees, A.J. (Andrew), Devlin, B. (Bernie), Hakonarson, H. (Hakon), Müller, U. (Ulrich), Schellenberg, G.D. (Gerard), Albin, R.L. (Roger), Alonso, E. (Elena), Apfelbacher, M. (Manuela), Arnold, S.E. (Steven), Avila, J. (Jesús), Beach, T.G. (Thomas), Beecher, S. (Sherry), Berg, D. (Daniela), Bird, T.D. (Thomas), Bogdanović, N. (Nenad), Boon, A.J.W. (Andrea), Bordelon, Y. (Yvette), Brice, A. (Alexis), Budka, H. (Herbert), Canesi, M. (Margherita), Chiu, W.Z. (Wang Zheng), Cilia, R. (Roberto), Colosimo, C. (Carlo), Deyn, P.P. (Peter) de, Yebenes, J.G. de, Donker Kaat, L. (Laura), Duara, R. (Ranjan), Durr, A., Engelborghs, S. (Sebastiaan), Fabbrini, G. (Giovanni), Finch, N.A. (Nicole), Flook, R. (Robyn), Frosch, M.P. (Matthew), Gaig, C., Galasko, D. (Douglas), Gasser, T. (Thomas), Gearing, M. (Marla), Geller, E.T. (Evan), Ghetti, B. (Bernardino), Graff-Radford, N.R. (Neill), Grossman, M. (Murray), Hall, D.A. (Deborah), Hazrati, L.-N., Höllerhage, M. (Matthias), Jankovic, J. (Joseph), Juncos, J.L. (Jorge), Karydas, A. (Anna), Kretzschmar, H.A. (Hans), Leber, I. (Isabelle), Lee, V.M.Y. (Virginia), Lieberman, A.P. (Andrew), Lyons, K.E. (Kelly), Mariani, C. (Claudio), Masliah, E. (Eliezer), Massey, L.A. (Luke), McLean, C.A. (Catriona), Meucci, N. (Nicoletta), Miller, B.L. (Bruce), Mollenhauer, B. (Brit), Möller, J.C. (Jens), Morris, H. (Huw), O'Sullivan, S.S. (Sean), Oertel, W., Ottaviani, D. (Donatella), Padovani, A. (Alessandro), Pahwa, R. (Rajesh), Pezzoli, G. (Gianni), Pickering-Brown, S. (Stuart), Poewe, W. (Werner), Rabano, A. (Alberto), Rajput, A. (Alex), Reich, S.G. (Stephen), Respondek, G. (Gesine), Roeber, S. (Sigrun), Rohrer, J.D. (Jonathan), Ross, O.A. (Owen), Rossor, M. (Martin), Sacilotto, G. (Giorgio), Seeley, W.W. (William), Seppi, K. (Klaus), Silveira-Moriyama, L. (Laura), Spina, S. (Salvatore), Srulijes, K. (Karin), St. George-Hyslop, P. (Peter), Stamelou, M. (Maria), Standaert, D.G. (David), Tesei, S. (Silvana), Tourtellotte, W.W. (Wallace), Trenkwalder, C. (Claudia), Troakes, C. (Claire), Trojanowski, J.Q. (John), Troncoso, J.C. (Juan), Deerlin, V.M. (Vivianna), Vonsattel, J.P.G., Wenning, G.K. (Gregor), White III, C.L. (Charles), Winter, P. (Pia), Zarow, C. (Chris), Zecchinelli, A.L. (Anna), Antonini, A. (Angelo), Hoglinger, G. (Gunter), Melhem, N.M. (Nadine), Dickson, D. (Dennis), Sleiman, P.M.A. (Patrick), Wang, L.S. (Li-San), Klei, L. (Lambertus), Rademakers, R. (Rosa), Silva, R. (Rohan) de, Litvan, I. (Irene), Riley, D.E. (David), Swieten, J.C. (John) van, Heutink, P. (Peter), Wszolek, Z.K. (Zbigniew), Uitti, R.J. (Ryan), Vandrovcova, J. (Jana), Hurtig, H.I. (Howard), Gross, R.G. (Rachel), Maetzler, W. (Walter), Goldwurm, S. (Stefano), Tolosa, E., Borroni, B. (Barbara), Pastor, P. (Pau), Cantwell, L.B. (Laura), Han, M.R., Dillman, A. (Allissa), Brug, M.P. (Marcel) van der, Gibbs, J. (Raphael), Cookson, M.R. (Mark), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Farrer, M.J. (Matthew), Yu, C.-E. (Changen), Golbe, L.I. (Lawrence), Revesz, T. (Tamas), Hardy, J. (John), Lees, A.J. (Andrew), Devlin, B. (Bernie), Hakonarson, H. (Hakon), Müller, U. (Ulrich), Schellenberg, G.D. (Gerard), Albin, R.L. (Roger), Alonso, E. (Elena), Apfelbacher, M. (Manuela), Arnold, S.E. (Steven), Avila, J. (Jesús), Beach, T.G. (Thomas), Beecher, S. (Sherry), Berg, D. (Daniela), Bird, T.D. (Thomas), Bogdanović, N. (Nenad), Boon, A.J.W. (Andrea), Bordelon, Y. (Yvette), Brice, A. (Alexis), Budka, H. (Herbert), Canesi, M. (Margherita), Chiu, W.Z. (Wang Zheng), Cilia, R. (Roberto), Colosimo, C. (Carlo), Deyn, P.P. (Peter) de, Yebenes, J.G. de, Donker Kaat, L. (Laura), Duara, R. (Ranjan), Durr, A., Engelborghs, S. (Sebastiaan), Fabbrini, G. (Giovanni), Finch, N.A. (Nicole), Flook, R. (Robyn), Frosch, M.P. (Matthew), Gaig, C., Galasko, D. (Douglas), Gasser, T. (Thomas), Gearing, M. (Marla), Geller, E.T. (Evan), Ghetti, B. (Bernardino), Graff-Radford, N.R. (Neill), Grossman, M. (Murray), Hall, D.A. (Deborah), Hazrati, L.-N., Höllerhage, M. (Matthias), Jankovic, J. (Joseph), Juncos, J.L. (Jorge), Karydas, A. (Anna), Kretzschmar, H.A. (Hans), Leber, I. (Isabelle), Lee, V.M.Y. (Virginia), Lieberman, A.P. (Andrew), Lyons, K.E. (Kelly), Mariani, C. (Claudio), Masliah, E. (Eliezer), Massey, L.A. (Luke), McLean, C.A. (Catriona), Meucci, N. (Nicoletta), Miller, B.L. (Bruce), Mollenhauer, B. (Brit), Möller, J.C. (Jens), Morris, H. (Huw), O'Sullivan, S.S. (Sean), Oertel, W., Ottaviani, D. (Donatella), Padovani, A. (Alessandro), Pahwa, R. (Rajesh), Pezzoli, G. (Gianni), Pickering-Brown, S. (Stuart), Poewe, W. (Werner), Rabano, A. (Alberto), Rajput, A. (Alex), Reich, S.G. (Stephen), Respondek, G. (Gesine), Roeber, S. (Sigrun), Rohrer, J.D. (Jonathan), Ross, O.A. (Owen), Rossor, M. (Martin), Sacilotto, G. (Giorgio), Seeley, W.W. (William), Seppi, K. (Klaus), Silveira-Moriyama, L. (Laura), Spina, S. (Salvatore), Srulijes, K. (Karin), St. George-Hyslop, P. (Peter), Stamelou, M. (Maria), Standaert, D.G. (David), Tesei, S. (Silvana), Tourtellotte, W.W. (Wallace), Trenkwalder, C. (Claudia), Troakes, C. (Claire), Trojanowski, J.Q. (John), Troncoso, J.C. (Juan), Deerlin, V.M. (Vivianna), Vonsattel, J.P.G., Wenning, G.K. (Gregor), White III, C.L. (Charles), Winter, P. (Pia), Zarow, C. (Chris), Zecchinelli, A.L. (Anna), and Antonini, A. (Angelo)

Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopath

Published
2011
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28. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations

Author

Neumann, M, Bentmann, E, Dormann, D, Jawaid, A, DeJesus-Hernandez, M, Ansorge, O, Roeber, S, Kretzschmar, H A, Munoz, D G, Kusaka, H, Yokota, O, Ang, L C, Bilbao, J, Rademakers, R, Haass, C, Mackenzie, I R A, Neumann, M, Bentmann, E, Dormann, D, Jawaid, A, DeJesus-Hernandez, M, Ansorge, O, Roeber, S, Kretzschmar, H A, Munoz, D G, Kusaka, H, Yokota, O, Ang, L C, Bilbao, J, Rademakers, R, Haass, C, and Mackenzie, I R A

Abstract

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration w

Published
2011

30. A new subtype of frontotemporal lobar degeneration with FUS pathology

Author

Neumann, M, Rademakers, R, Roeber, S, Baker, M, Kretzschmar, H A, Mackenzie, I R A, Neumann, M, Rademakers, R, Roeber, S, Baker, M, Kretzschmar, H A, and Mackenzie, I R A

Abstract

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein. However, we recently described a subgroup of FTD patients, representing around 10%, with an unusual clinical phenotype and pathology characterized by frontotemporal lobar degeneration with neuronal inclusions composed of an unidentified ubiquitinated protein (atypical FTLD-U; aFTLD-U). All cases were sporadic and had early-onset FTD with severe progressive behavioural and personality changes in the absence of aphasia or significant motor features. Mutations in the fused in sarcoma (FUS) gene have recently been identified as a cause of familial amyotrophic lateral sclerosis, with these cases reported to have abnormal cellular accumulations of FUS protein. Because of the recognized clinical, genetic and pathological overlap between FTD and amyotrophic lateral sclerosis, we investigated whether FUS might also be the pathological protein in aFTLD-U. In all our aFTLD-U cases (n = 15), FUS immunohistochemistry labelled all the neuronal inclusions and also demonstrated previously unrecognized glial pathology. Immunoblot analysis of protein extracted from post-mortem aFTLD-U brain tissue demonstrated increased levels of insoluble FUS. No mutations in the FUS gene were identified in any of our patients. These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and amyotrophic lateral sclerosis are closely related conditions.

Published
2009

31. MRI characteristics and scoring in HDLS due to CSF1R gene mutations

Author

Sundal, C., primary, Van Gerpen, J. A., additional, Nicholson, A. M., additional, Wider, C., additional, Shuster, E. A., additional, Aasly, J., additional, Spina, S., additional, Ghetti, B., additional, Roeber, S., additional, Garbern, J., additional, Borjesson-Hanson, A., additional, Tselis, A., additional, Swerdlow, R. H., additional, Miller, B. B., additional, Fujioka, S., additional, Heckman, M. G., additional, Uitti, R. J., additional, Josephs, K. A., additional, Baker, M., additional, Andersen, O., additional, Rademakers, R., additional, Dickson, D. W., additional, Broderick, D., additional, and Wszolek, Z. K., additional

Published
2012
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32. HDLS: Due to CSF1R Gene Mutation; Clinical Characteristics (P05.119)

Author

Sundal, C., primary, Van Gerpen, J., additional, Fujioka, S., additional, Aasly, J., additional, Wider, C., additional, Roeber, S., additional, Shuster, E., additional, Ghetti, B., additional, Garbern, J., additional, Tselis, A., additional, Swerdlow, R., additional, Rademakers, R., additional, Dickson, D., additional, Broderick, D., additional, and Wszolek, Z., additional

Published
2012
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34. Observational Study for MRI Characteristics in HDLS with a Known Gene Mutation on Chromosome 5 (P06.180)

Author

Sundal, C., primary, Fujioka, S., additional, Van Gerpen, J., additional, Wider, C., additional, Aasly, J., additional, Roeber, S., additional, Shuster, E., additional, Ghetti, B., additional, Garbern, J., additional, Tselis, A., additional, Swerdlow, R., additional, Miller, B., additional, Rademakers, R., additional, Dickson, D., additional, Broderick, D., additional, and Wszolek, Z., additional

Published
2012
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35. Identification of a second major locus for neurodegeneration with brain iron accumulation

Author

Hartig, MB, primary, Iuso, A, additional, Kmiec, T, additional, Jurkiewicz, E, additional, Heim, K, additional, Roeber, S, additional, Krajewska-Walasek, M, additional, Jozwiak, S, additional, Hempel, M, additional, Winkelmann, J, additional, Haack, T, additional, Elstner, M, additional, Oexle, K, additional, Klopstock, T, additional, Mueller-Felber, W, additional, Kretzschmar, H, additional, Strom, TM, additional, Meitinger, T, additional, and Prokisch, H, additional

Published
2011
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36. P117 Atypical clinical presentation in postmortem validated PSP

Author

Respondek, G., primary, Roeber, S., additional, Apfelbacher, M., additional, Gelpi, E., additional, Gaig, C., additional, Troakes, C., additional, Chiu, W., additional, van Swieten, J., additional, Rajput, A., additional, Kretzschmar, H., additional, Oertel, W.H., additional, and Höglinger, G., additional

Published
2011
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37. Cerebral angiitis in four patients with chronic GVHD

Author

Sostak, P, primary, Padovan, C S, additional, Eigenbrod, S, additional, Roeber, S, additional, Segerer, S, additional, Schankin, C, additional, Siegert, S, additional, Saam, T, additional, Theil, D, additional, Kolb, H-J, additional, Kretzschmar, H, additional, and Straube, A, additional

Published
2009
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42. Next-Generation Sequencing Reveals Regional Differences of the α-Synuclein Methylation State Independent of Lewy Body Disease.

Author

Boni, L., Tierling, S., Roeber, S., Walter, J., Giese, A., and Kretzschmar, Hans

Abstract

The α-synuclein gene ( SNCA) plays a major role in the aetiology of Lewy body disease (LBD) including Parkinson's disease (PD). Point mutations and genetic alterations causing elevated gene expression are causally linked to familial PD. To what extent epigenetic changes play a role in the regulation of α-synuclein expression and may contribute to the aetiology of sporadic LBD is a matter of debate. We analysed the methylation state of the promoter region and a CpG-rich region of intron 1 of α-synuclein in several brain regions in sporadic LBD and controls using 454 GS-FLX-based high-resolution bisulphite sequencing. Our results indicate that there are significant differences in the level of methylation between different brain areas. The overall methylation levels in the promoter and intron 1 of α-synuclein are rather low in controls and-in contrast to previously reported findings-are not significantly different from LBD. However, single CpG analysis revealed significant hyper- and hypomethylation at different positions in various brain regions and LBD stages. A slight overall increase in methylation related to LBD patients' age was detected. [ABSTRACT FROM AUTHOR]

Published
2011
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43. Clinical features of rapidly progressive Alzheimer's disease.

Author

Schmidt C, Redyk K, Meissner B, Krack L, von Ahsen N, Roeber S, Kretzschmar H, and Zerr I

Abstract

Objective: To characterize clinical features, CSF biomarkers and genetic polymorphisms of patients suffering from a rapidly progressing subtype of Alzheimer's dementia (rpAD). Methods: Retrospective analyses of 32 neuropathologically confirmed cases differentially diagnosed as AD out of a group with rapidly progressive dementia. CSF biomarkers (14-3-3, tau, [beta]-amyloid 1-42) and genetic markers (PRNP codon 129, apolipoprotein E, ApoE, polymorphism) were determined. Results: Median survival was 26 months, age at onset 73 years. Biomarkers: mean [beta]-amyloid 1-42: 266 pg/ml, median tau: 491 pg/ml, 14-3-3 positive: 31%. Genetic polymorphisms showed a predominance of methionine homozygosity at PRNP codon 129 and a low frequency of ApoE4 (38%, no homozygous patients). Thirty-five symptoms were studied. Frequent symptoms were myoclonus (75%), disturbed gait (66%) and rigidity (50%). Discussion: rpAD is associated with a diversity of neurological signs even able to mimic Creutzfeldt-Jakob disease. Biomarkers and genetic profile differ from those seen in classical AD. The findings on biomarkers, symptomatology and genetics may aid the differential diagnostic process. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Published
2010
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46. Are nurse-to-patient ratios the best way to improve patient care?

Author

Burch, Paula, Edwards, Lynnette, Burghardt, James, Mangham, Julie, Roeber, S., Boettcher, Holly, Fuller, Sonia, and Wilson, Kathleen

Subjects
NURSE practitioners, PATIENTS, NURSE-patient relationships, NURSING practice, MEDICAL care
Abstract

The article presents the opinions of nurse practitioners whether nurse-to-patient ratio is the best way to improve patient care. Paula Burch answered yes but acuity, patient types, equipment, skills mix and availability of ancillary staff need to be incorporated into the ratio. James Burghardt stated that it depends as ratios are just one tool to promote care and nurse retention. S. Roeber says no as patient care should be based on acuity.

Published
2007

49. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study

Author

Andreas Charidimou, Gregoire Boulouis, Matthew P Frosch, Jean-Claude Baron, Marco Pasi, Jean Francois Albucher, Gargi Banerjee, Carmen Barbato, Fabrice Bonneville, Sebastian Brandner, Lionel Calviere, François Caparros, Barbara Casolla, Charlotte Cordonnier, Marie-Bernadette Delisle, Vincent Deramecourt, Martin Dichgans, Elif Gokcal, Jochen Herms, Mar Hernandez-Guillamon, Hans Rolf Jäger, Zane Jaunmuktane, Jennifer Linn, Sergi Martinez-Ramirez, Elena Martínez-Sáez, Christian Mawrin, Joan Montaner, Solene Moulin, Jean-Marc Olivot, Fabrizio Piazza, Laurent Puy, Nicolas Raposo, Mark A Rodrigues, Sigrun Roeber, Jose Rafael Romero, Neshika Samarasekera, Julie A Schneider, Stefanie Schreiber, Frank Schreiber, Corentin Schwall, Colin Smith, Levente Szalardy, Pascale Varlet, Alain Viguier, Joanna M Wardlaw, Andrew Warren, Frank A Wollenweber, Marialuisa Zedde, Mark A van Buchem, M Edip Gurol, Anand Viswanathan, Rustam Al-Shahi Salman, Eric E Smith, David J Werring, Steven M Greenberg, Charidimou, A, Boulouis, G, Frosch, M, Baron, J, Pasi, M, Albucher, J, Banerjee, G, Barbato, C, Bonneville, F, Brandner, S, Calviere, L, Caparros, F, Casolla, B, Cordonnier, C, Delisle, M, Deramecourt, V, Dichgans, M, Gokcal, E, Herms, J, Hernandez-Guillamon, M, Jäger, H, Jaunmuktane, Z, Linn, J, Martinez-Ramirez, S, Martínez-Sáez, E, Mawrin, C, Montaner, J, Moulin, S, Olivot, J, Piazza, F, Puy, L, Raposo, N, Rodrigues, M, Roeber, S, Romero, J, Samarasekera, N, Schneider, J, Schreiber, S, Schreiber, F, Schwall, C, Smith, C, Szalardy, L, Varlet, P, Viguier, A, Wardlaw, J, Warren, A, Wollenweber, F, Zedde, M, van Buchem, M, Gurol, M, Viswanathan, A, Al-Shahi Salman, R, Smith, E, Werring, D, and Greenberg, S

Subjects
diagnoisi, Amyloid beta-Peptides, pathology [Cerebral Hemorrhage], Middle Aged, MED/46 - SCIENZE TECNICHE DI MEDICINA DI LABORATORIO, Magnetic Resonance Imaging, diagnostic imaging [Cerebral Amyloid Angiopathy], Cerebral Amyloid Angiopathy, methods [Magnetic Resonance Imaging], biomarker, Humans, Neurology (clinical), ddc:610, Neuropathology, MRI, Aged, Cerebral Hemorrhage, Retrospective Studies
Abstract

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations.METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy.FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard.INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations.FUNDING: US National Institutes of Health (R01 AG26484).

Published
2021
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50. Neuronal and oligodendroglial, but not astroglial, tau translates to in vivo tau PET signals in individuals with primary tauopathies.

Author

Slemann L, Gnörich J, Hummel S, Bartos LM, Klaus C, Kling A, Kusche-Palenga J, Kunte ST, Kunze LH, Englert AL, Li Y, Vogler L, Katzdobler S, Palleis C, Bernhardt A, Jäck A, Zwergal A, Hopfner F, Roemer-Cassiano SN, Biechele G, Stöcklein S, Bischof G, van Eimeren T, Drzezga A, Sabri O, Barthel H, Respondek G, Grimmer T, Levin J, Herms J, Paeger L, Willroider M, Beyer L, Höglinger GU, Roeber S, Franzmeier N, and Brendel M

Subjects
Humans, Animals, Male, Female, Aged, Mice, Middle Aged, Mice, Transgenic, Supranuclear Palsy, Progressive diagnostic imaging, Supranuclear Palsy, Progressive metabolism, Supranuclear Palsy, Progressive pathology, Brain metabolism, Brain diagnostic imaging, Brain pathology, Disease Models, Animal, tau Proteins metabolism, Positron-Emission Tomography methods, Astrocytes metabolism, Astrocytes pathology, Tauopathies diagnostic imaging, Tauopathies pathology, Tauopathies metabolism, Neurons metabolism, Neurons pathology, Oligodendroglia metabolism, Oligodendroglia pathology
Abstract

Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau PET signals is still unclear. Therefore, we performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [ 18 F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [ 18 F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [ 18 F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [ 18 F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2-63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [ 18 F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal., Competing Interests: Declarations. Conflict of interest: MB is a member of the Neuroimaging Committee of the EANM. MB has received speaker honoraria from Roche, GE Healthcare, and Life Molecular Imaging; has advised Life Molecular Imaging; and is currently on the advisory board of MIAC. NF received speaker honoraria from Eisai and Life Molecular Imaging and consulting honoraria from MSD. CP and JL are inventors in the patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. JL reports speaker fees from Bayer Vital, Biogen and Roche; consulting fees from Axon Neuroscience and Biogen; author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers; nonfinancial support from AbbVie; and compensation for duty as part-time CMO from MODAG, all outside the submitted work. TvE reports speaker/consultant fees from Eli Lilly, Shire, H. Lundbeck A/S, and Orion Corporation, and author fees from Thieme Medical Publishers, all without conflicts of interest with regard to the submitted work. Gesine Respondek has been a full-time employee at Roche Pharmaceuticals since July 2021 and has consulted for UCB, all outside of the submitted work. AZ reports speaker fees and research support from Dr. Willmar Schwabe GmbH and author fees from Thieme Medical Publishers, Springer Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition to the submitted work, TG received consulting fees from AbbVie, Alector, Anavex, Biogen, BMS, Cogthera, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Janssen, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche Pharma, UCB, and Vivoryon; lecture fees from Biogen, Eisai, Grifols, Medical Tribune, Novo Nordisk, Roche Pharma, Schwabe, and Synlab; and grants to his institution from Biogen, Eisai, and Roche Diagnostics. LB is a Novartis Pharma GmbH employee, unrelated to this work. All the other authors declare that no conflicts of interest exist., (© 2024. The Author(s).)

Published
2024
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