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3. Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort

Author

Heuer, Hilary W, Wang, P, Rascovsky, K, Wolf, A, Appleby, B, Bove, J, Bordelon, Y, Brannelly, P, Brushaber, DE, Caso, C, Coppola, G, Dickerson, B, Dickinson, S, Domoto‐Reilly, K, Faber, K, Ferrall, J, Fields, J, Fishman, A, Fong, J, Foroud, T, Forsberg, LK, Gearhart, D, Ghazanfari, B, Ghoshal, N, Goldman, J, Graff‐Radford, J, Graff‐Radford, N, Grant, I, Grossman, M, Haley, D, Hsiung, G‐Y, Huey, E, Irwin, D, Jones, D, Kantarci, K, Karydas, A, Kaufer, D, Kerwin, D, Knopman, D, Kornak, J, Kramer, JH, Kraft, R, Kremers, WK, Kukull, W, Litvan, I, Ljubenkov, P, Mackenzie, IR, Maldonado, M, Manoochehri, M, McGinnis, S, McKinley, E, Mendez, MF, Miller, BL, Onyike, C, Pantelyat, A, Pearlman, R, Petrucelli, L, Potter, M, Rademakers, R, Ramos, EM, Rankin, KP, Roberson, ED, Rogalski, E, Sengdy, P, Shaw, L, Syrjanen, J, Tartaglia, MC, Tatton, N, Taylor, J, Toga, A, Trojanowski, J, Weintraub, S, Wong, B, Wszolek, Z, Boeve, BF, Rosen, HJ, Boxer, AL, and consortia, on behalf of the ARTFL and LEFFTDS

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Aging, Behavioral and Social Science, Rare Diseases, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Neurodegenerative, Dementia, Clinical Research, Acquired Cognitive Impairment, Brain Disorders, Frontotemporal Dementia (FTD), Neurological, Age Factors, Aged, Brain, C9orf72 Protein, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Neuropsychological Tests, North America, Progranulins, tau Proteins, bvFTD, C9orf72, clinical trials, frontotemporal dementia, genetics, GRN, MAPT, ARTFL and LEFFTDS consortia, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Published
2020

4. Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration

Author

Casaletto, KB, Staffaroni, AM, Wolf, A, Appleby, B, Brushaber, D, Coppola, G, Dickerson, B, Domoto‐Reilly, K, Elahi, FM, Fields, J, Fong, JC, Forsberg, L, Ghoshal, N, Graff‐Radford, N, Grossman, M, Heuer, HW, Hsiung, G‐Y, Huey, ED, Irwin, D, Kantarci, K, Kaufer, D, Kerwin, D, Knopman, D, Kornak, J, Kramer, JH, Litvan, I, Mackenzie, IR, Mendez, M, Miller, B, Rademakers, R, Ramos, EM, Rascovsky, K, Roberson, ED, Syrjanen, JA, Tartaglia, MC, Weintraub, S, Boeve, B, Boxer, AL, Rosen, H, Yaffe, K, and Study, the ARTFL LEFFTDS

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Basic Behavioral and Social Science, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Neurodegenerative, Clinical Research, Brain Disorders, Prevention, Frontotemporal Dementia (FTD), Behavioral and Social Science, Biomedical Imaging, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease, Neurosciences, Acquired Cognitive Impairment, Dementia, Neurological, Aged, Atrophy, Cognition, Exercise, Female, Frontotemporal Lobar Degeneration, Humans, Leisure Activities, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, cognitive activity, cognitive reserve, exercise, frontotemporal dementia, physical activity, ARTFL/LEFFTDS Study, Clinical Sciences, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionLeisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsA total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.ResultsGreater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.DiscussionActive lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Published
2020

6. An Authentication Technique in Frequency Domain through Wavelet Transform (ATFDWT)

Author

Sengupta, Madhumita, Mandal, J. K., and Ghoshal, N.

Subjects
Computer Science - Cryptography and Security
Abstract

In this paper a DWT based steganography in frequency domain, termed as ATFDWT has been proposed. Here, the cover image is transformed into the time domain signal through DWT, resulting four sub-image components as 'Low resolution', 'Horizontal orientation', 'Vertical orientation' and 'Diagonal orientation'. The secret message/image bits stream in varying positions are embedded in 'Vertical orientation sub-image' followed by reverse transformation to generate embedded/encrypted image. The decoding is done through the reverse procedure. The experimental results against statistical and visual attack has been computed and compared with the existing technique like IAFDDFTT[1], in terms of Mean Square Error (MSE), Peak Signal to Noise Ratio (PSNR), Standard Deviation(SD) and Image Fidelity(IF) analysis, which shows better performances in ATFDWT., Comment: 18 Page Journal in 'Advances in Modelling Signal Processing and Pattern Recognition' (AMSE), vol-54, Issue 2, 20011

Published
2012

8. REGISTRIES AND CARE OF NMD

Author

Korb, M., primary, Peck, A., additional, Berger, K., additional, James, M., additional, Ghoshal, N., additional, Healzer, E., additional, Henchcliffe, C., additional, Khan, S., additional, Mammen, P., additional, Patel, S., additional, Pfeffer, G., additional, Ralston, S., additional, Roy, B., additional, Seeley, B., additional, Swenson, A., additional, Mozaffar, T., additional, Weihl, C., additional, Kimonis, V., additional, and Alfano, L., additional

Published
2021
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9. Gearing up for the future: Exploring facilitators and barriers to inform clinical trial design in frontotemporal lobar degeneration

Author

Banga, YB, Banga, YB, Lai, Y, Kim, P, Boeve, BF, Boxer, AL, Rosen, HJ, Forsberg, LK, Heuer, HW, Brushaber, D, Appleby, B, Biernacka, JM, Bordelon, YM, Botha, H, Bozoki, AC, Brannelly, P, Dickerson, BC, Dickinson, S, Dickson, DW, Domoto-Reilly, K, Faber, K, Fagan, AM, Fields, JA, Fishman, A, Foroud, TM, Galasko, DR, Gavrilova, RH, Gendron, TF, Geschwind, DH, Ghoshal, N, Goldman, J, Graff-Radford, J, Graff-Radford, NR, Grant, I, Grossman, M, Hsiung, GYR, Huang, EJ, Huey, ED, Irwin, DJ, Jones, DT, Kantarci, K, Karydas, AM, Kaufer, D, Knopman, DS, Kramer, JH, Kremers, WK, Kornak, J, Kukull, WA, Lagone, E, Leger, GC, Litvan, I, Ljubenkov, PA, Lucente, DE, Mackenzie, IR, Manoochehri, M, Masdeu, JC, McGinnis, S, Mendez, MF, Miller, BL, Miyagawa, T, Nelson, KM, Onyike, CU, Pantelyat, A, Pascual, B, Pearlman, R, Petrucelli, L, Pottier, CP, Rademakers, R, Ramos, EM, Rankin, KP, Rascovsky, K, Rexach, JE, Ritter, A, Roberson, ED, Rojas, JC, Sabbagh, MN, Salmon, DP, Savica, R, Seeley, WW, Staffaroni, AM, Syrjanen, JA, Tartaglia, MC, Tatton, N, Taylor, JC, Toga, AW, Weintraub, S, Wheaton, D, Wong, B, Wszolek, Z, Banga, YB, Banga, YB, Lai, Y, Kim, P, Boeve, BF, Boxer, AL, Rosen, HJ, Forsberg, LK, Heuer, HW, Brushaber, D, Appleby, B, Biernacka, JM, Bordelon, YM, Botha, H, Bozoki, AC, Brannelly, P, Dickerson, BC, Dickinson, S, Dickson, DW, Domoto-Reilly, K, Faber, K, Fagan, AM, Fields, JA, Fishman, A, Foroud, TM, Galasko, DR, Gavrilova, RH, Gendron, TF, Geschwind, DH, Ghoshal, N, Goldman, J, Graff-Radford, J, Graff-Radford, NR, Grant, I, Grossman, M, Hsiung, GYR, Huang, EJ, Huey, ED, Irwin, DJ, Jones, DT, Kantarci, K, Karydas, AM, Kaufer, D, Knopman, DS, Kramer, JH, Kremers, WK, Kornak, J, Kukull, WA, Lagone, E, Leger, GC, Litvan, I, Ljubenkov, PA, Lucente, DE, Mackenzie, IR, Manoochehri, M, Masdeu, JC, McGinnis, S, Mendez, MF, Miller, BL, Miyagawa, T, Nelson, KM, Onyike, CU, Pantelyat, A, Pascual, B, Pearlman, R, Petrucelli, L, Pottier, CP, Rademakers, R, Ramos, EM, Rankin, KP, Rascovsky, K, Rexach, JE, Ritter, A, Roberson, ED, Rojas, JC, Sabbagh, MN, Salmon, DP, Savica, R, Seeley, WW, Staffaroni, AM, Syrjanen, JA, Tartaglia, MC, Tatton, N, Taylor, JC, Toga, AW, Weintraub, S, Wheaton, D, Wong, B, and Wszolek, Z

Abstract

BACKGROUND: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates. OBJECTIVE: The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. METHODS: Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation. RESULTS: 29% of respondents self-reported as patients (63±10 years), 26% self-reported as caregivers answering on behalf of patients (65±10 years), and 45% self-reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture

Published
2021

10. Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy

Author

Korb, M, Korb, M, Peck, A, Berger, K, James, M, Ghoshal, N, Healzer, E, Henchcliffe, C, Khan, S, Mammen, P, Patel, S, Pfeffer, G, Ralston, S, Roy, B, Seeley, B, Swenson, A, Mozaffar, T, Weihl, C, Kimonis, V, Alfano, L, Korb, M, Korb, M, Peck, A, Berger, K, James, M, Ghoshal, N, Healzer, E, Henchcliffe, C, Khan, S, Mammen, P, Patel, S, Pfeffer, G, Ralston, S, Roy, B, Seeley, B, Swenson, A, Mozaffar, T, Weihl, C, Kimonis, V, and Alfano, L

Published
2021

11. Demographic and psychosocial factors associated with the decision to learn mutation status in familial frontotemporal dementia and the impact of disclosure on mood

Author

Bajorek, LP, Bajorek, LP, Kiekhofer, R, Hall, M, Taylor, J, Lucente, DE, Brushaber, D, Appleby, B, Coppolla, G, Bordelon, YM, Botha, H, Dickerson, BC, Dickson, DW, Domoto-Reilly, K, Fagan, AM, Fields, JA, Fong, JC, Foroud, TM, Forsberg, LK, Galasko, DR, Gavrilova, RH, Geschwind, DH, Ghoshal, N, Goldman, J, Graff-Radford, NR, Graff-Radford, J, Grant, I, Grossman, M, Heuer, HW, Hsiung, GYR, Huang, EJ, Huey, ED, Irwin, DJ, Jones, DT, Kantarci, K, Kornak, J, Kremers, WK, Lapid, MI, Leger, GC, Litvan, I, Ljubenkov, PA, Mackenzie, IR, Masdeu, JC, McMillan, C, Mendez, M, Miller, BL, Miyagawa, T, Onyike, CU, Pascual, B, Pedraza, O, Petrucelli, L, Rademakers, R, Ramos, EM, Rankin, KP, Rascovsky, K, Rexach, JE, Ritter, A, Roberson, ED, Savica, R, Rojas, JC, Seeley, WW, Tartaglia, MC, Toga, AW, Weintraub, S, Wong, B, Wszolek, Z, Vandevrede, L, Boeve, BF, Boxer, AL, Rosen, HJ, Staffaroni, AM, Bajorek, LP, Bajorek, LP, Kiekhofer, R, Hall, M, Taylor, J, Lucente, DE, Brushaber, D, Appleby, B, Coppolla, G, Bordelon, YM, Botha, H, Dickerson, BC, Dickson, DW, Domoto-Reilly, K, Fagan, AM, Fields, JA, Fong, JC, Foroud, TM, Forsberg, LK, Galasko, DR, Gavrilova, RH, Geschwind, DH, Ghoshal, N, Goldman, J, Graff-Radford, NR, Graff-Radford, J, Grant, I, Grossman, M, Heuer, HW, Hsiung, GYR, Huang, EJ, Huey, ED, Irwin, DJ, Jones, DT, Kantarci, K, Kornak, J, Kremers, WK, Lapid, MI, Leger, GC, Litvan, I, Ljubenkov, PA, Mackenzie, IR, Masdeu, JC, McMillan, C, Mendez, M, Miller, BL, Miyagawa, T, Onyike, CU, Pascual, B, Pedraza, O, Petrucelli, L, Rademakers, R, Ramos, EM, Rankin, KP, Rascovsky, K, Rexach, JE, Ritter, A, Roberson, ED, Savica, R, Rojas, JC, Seeley, WW, Tartaglia, MC, Toga, AW, Weintraub, S, Wong, B, Wszolek, Z, Vandevrede, L, Boeve, BF, Boxer, AL, Rosen, HJ, and Staffaroni, AM

Abstract

BACKGROUND: Up to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f-FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f-FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice. METHOD: F-FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent-sample t-tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow-up), linear mixed effects modeling was used to investigate pre- to post-disclosure changes in the 15-item Geriatric Depression Scale (GDS). RESULT: Of participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non-learners (p's > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre- to post-increase of 0.31 GDS points/year (95%CI: -0.08, 0.69, p = 0.12), whereas non-learners showed a slight decline (-0.15 points/year, 95%CI: -0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%

Published
2021

12. Brain volumetric deficits in MAPT mutation carriers: a multisite study

Author

Chu, SA, Flagan, TM, Staffaroni, AM, Jiskoot, Lize, Deng, J, Spina, S, Zhang, L, Sturm, VE, Yokoyama, JS, Seeley, WW, Papma, Janne, Geschwind, DH, Rosen, HJ, Boeve, BF, Boxer, AL, Heuer, HW, Forsberg, LK, Brushaber, DE, Grossman, M, Coppola, G, Dickerson, BC, Bordelon, YM, Faber, K, Feldman, HH, Fields, JA, Fong, JC, Foroud, T, Gavrilova, RH, Ghoshal, N, Graff-Radford, NR, Hsiung, GYR, Huey, ED, Irwin, DJ, Kantarci, K, Kaufer, DI, Karydas, AM, Knopman, DS, Kornak, J, Kramer, JH, Kukull, WA, Lapid, MI, Litvan, I, Mackenzie, IRA, Mendez, MF, Miller, BL, Onyike, CU, Pantelyat, AY, Rademakers, R, Ramos, E, Roberson, ED, Tartaglia, M, Tatton, NA, Toga, AW, Vetor, A, Weintraub, S, Wong, B, Wszolek, ZK, van Swieten, J.C., Lee, SE, Chu, SA, Flagan, TM, Staffaroni, AM, Jiskoot, Lize, Deng, J, Spina, S, Zhang, L, Sturm, VE, Yokoyama, JS, Seeley, WW, Papma, Janne, Geschwind, DH, Rosen, HJ, Boeve, BF, Boxer, AL, Heuer, HW, Forsberg, LK, Brushaber, DE, Grossman, M, Coppola, G, Dickerson, BC, Bordelon, YM, Faber, K, Feldman, HH, Fields, JA, Fong, JC, Foroud, T, Gavrilova, RH, Ghoshal, N, Graff-Radford, NR, Hsiung, GYR, Huey, ED, Irwin, DJ, Kantarci, K, Kaufer, DI, Karydas, AM, Knopman, DS, Kornak, J, Kramer, JH, Kukull, WA, Lapid, MI, Litvan, I, Mackenzie, IRA, Mendez, MF, Miller, BL, Onyike, CU, Pantelyat, AY, Rademakers, R, Ramos, E, Roberson, ED, Tartaglia, M, Tatton, NA, Toga, AW, Vetor, A, Weintraub, S, Wong, B, Wszolek, ZK, van Swieten, J.C., and Lee, SE

Abstract

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Published
2021

14. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author

Moore, K.M. Nicholas, J. Grossman, M. McMillan, C.T. Irwin, D.J. Massimo, L. Van Deerlin, V.M. Warren, J.D. Fox, N.C. Rossor, M.N. Mead, S. Bocchetta, M. Boeve, B.F. Knopman, D.S. Graff-Radford, N.R. Forsberg, L.K. Rademakers, R. Wszolek, Z.K. van Swieten, J.C. Jiskoot, L.C. Meeter, L.H. Dopper, E.G. Papma, J.M. Snowden, J.S. Saxon, J. Jones, M. Pickering-Brown, S. Le Ber, I. Camuzat, A. Brice, A. Caroppo, P. Ghidoni, R. Pievani, M. Benussi, L. Binetti, G. Dickerson, B.C. Lucente, D. Krivensky, S. Graff, C. Öijerstedt, L. Fallström, M. Thonberg, H. Ghoshal, N. Morris, J.C. Borroni, B. Benussi, A. Padovani, A. Galimberti, D. Scarpini, E. Fumagalli, G.G. Mackenzie, I.R. Hsiung, G.-Y.R. Sengdy, P. Boxer, A.L. Rosen, H. Taylor, J.B. Synofzik, M. Wilke, C. Sulzer, P. Hodges, J.R. Halliday, G. Kwok, J. Sanchez-Valle, R. Lladó, A. Borrego-Ecija, S. Santana, I. Almeida, M.R. Tábuas-Pereira, M. Moreno, F. Barandiaran, M. Indakoetxea, B. Levin, J. Danek, A. Rowe, J.B. Cope, T.E. Otto, M. Anderl-Straub, S. de Mendonça, A. Maruta, C. Masellis, M. Black, S.E. Couratier, P. Lautrette, G. Huey, E.D. Sorbi, S. Nacmias, B. Laforce, R., Jr Tremblay, M.-P.L. Vandenberghe, R. Damme, P.V. Rogalski, E.J. Weintraub, S. Gerhard, A. Onyike, C.U. Ducharme, S. Papageorgiou, S.G. Ng, A.S.L. Brodtmann, A. Finger, E. Guerreiro, R. Bras, J. Rohrer, J.D. Heller, C. Convery, R.S. Woollacott, I.O. Shafei, R.M. Graff-Radford, J. Jones, D.T. Dheel, C.M. Savica, R. Lapid, M.I. Baker, M. Fields, J.A. Gavrilova, R. Domoto-Reilly, K. Poos, J.M. Van der Ende, E.L. Panman, J.L. Donker Kaat, L. Seelaar, H. Richardson, A. Frisoni, G. Mega, A. Fostinelli, S. Chiang, H.-H. Alberici, A. Arighi, A. Fenoglio, C. Heuer, H. Miller, B. Karydas, A. Fong, J. João Leitão, M. Santiago, B. Duro, D. Ferreira, C. Gabilondo, A. De Arriba, M. Tainta, M. Zulaica, M. Ferreira, C. Semler, E. Ludolph, A. Landwehrmeyer, B. Volk, A.E. Miltenberger, G. Verdelho, A. Afonso, S. Tartaglia, M.C. Freedman, M. Rogaeva, E. Ferrari, C. Piaceri, I. Bessi, V. Lombardi, G. St-Onge, F. Doré, M.-C. Bruffaerts, R. Vandenbulcke, M. Van den Stock, J. Mesulam, M.M. Bigio, E. Koros, C. Papatriantafyllou, J. Kroupis, C. Stefanis, L. Shoesmith, C. Robertson, E. Coppola, G. Da Silva Ramos, E.M. Geschwind, D.

Abstract

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35–62, for age at onset; 61%, 47–73, for age at death), and even more by family membership (66%, 56–75, for age at onset; 74%, 65–82, for age at death). In the GRN group, only 2% (0–10) of the variability of age at onset and 9% (3–21) of that of age of death was explained by the specific mutation, whereas 14% (9–22) of the variability of age at onset and 20% (12–30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11–26) of the variability of age at onset and 19% (12–29) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society. © 2020 Elsevier Ltd

Published
2020

15. Brain volumetric deficits in MAPT mutation carriers: a multisite study

Author

Chu, S.A. (Stephanie A.), Flagan, T.M. (Taru M.), Staffaroni, A.M. (Adam M.), Jiskoot, L.C. (Lize), Deng, J. (Jersey), Spina, S. (Salvatore), Zhang, L. (Liwen), Sturm, V.E. (Virginia E.), Yokoyama, J.S. (Jennifer S.), Seeley, W.W. (William W.), Papma, J.M. (Janne), Geschwind, H., Rosen, H.J. (Howard J.), Boeve, B.F. (Bradley F.), Boxer, A.L. (Adam), Heuer, H.W. (Hilary W.), Forsberg, L.K. (Leah K.), Brushaber, D.E. (Danielle E.), Grossman, M. (Murray), Coppola, G. (Giovanni), Dickerson, F. (Faith), Bordelon, Y.M. (Yvette M.), Faber, K. (Kelley), Feldman, H.H. (Howard), Fields, J.A. (Julie A.), Fong, J.C. (Jamie C.), Foroud, T. (Tatiana), Gavrilova, R.H. (Ralitza H.), Ghoshal, N. (Nupur), Graff-Radford, N.R. (Neill), Hsiung, G.Y.R. (Ging-Yuek), Huey, E.D. (Edward), Irwin, D.J. (David J.), Kantarci, K. (Kejal), Kaufer, D.I. (Daniel I.), Karydas, A.M. (Anna M.), Knopman, D.S. (David), Kornak, J. (John), Kramer, J.H. (Joel), Kukull, W.A., Lapid, M.I. (Maria I.), Litvan, I., Mackenzie, I.R.A. (Ian), Mendez, M.F. (Mario), Miller, B.L. (Bruce Lars), Onyike, C.U. (Chiadi), Pantelyat, A.Y. (Alexander Y.), Rademakers, S. (Suzanne), Marisa Ramos, E. (Eliana), Roberson, E.D. (Erik D.), Carmela Tartaglia, M. (Maria), Tatton, N.A. (Nadine A.), Toga, A.W. (Arthur), Vetor, A. (Ashley), Weintraub, S. (Sandra), Wong, B. (Bonnie), Wszolek, Z.K. (Zbigniew), Swieten, J.C. (John) van, Lee, S.E. (Suzee E.), Chu, S.A. (Stephanie A.), Flagan, T.M. (Taru M.), Staffaroni, A.M. (Adam M.), Jiskoot, L.C. (Lize), Deng, J. (Jersey), Spina, S. (Salvatore), Zhang, L. (Liwen), Sturm, V.E. (Virginia E.), Yokoyama, J.S. (Jennifer S.), Seeley, W.W. (William W.), Papma, J.M. (Janne), Geschwind, H., Rosen, H.J. (Howard J.), Boeve, B.F. (Bradley F.), Boxer, A.L. (Adam), Heuer, H.W. (Hilary W.), Forsberg, L.K. (Leah K.), Brushaber, D.E. (Danielle E.), Grossman, M. (Murray), Coppola, G. (Giovanni), Dickerson, F. (Faith), Bordelon, Y.M. (Yvette M.), Faber, K. (Kelley), Feldman, H.H. (Howard), Fields, J.A. (Julie A.), Fong, J.C. (Jamie C.), Foroud, T. (Tatiana), Gavrilova, R.H. (Ralitza H.), Ghoshal, N. (Nupur), Graff-Radford, N.R. (Neill), Hsiung, G.Y.R. (Ging-Yuek), Huey, E.D. (Edward), Irwin, D.J. (David J.), Kantarci, K. (Kejal), Kaufer, D.I. (Daniel I.), Karydas, A.M. (Anna M.), Knopman, D.S. (David), Kornak, J. (John), Kramer, J.H. (Joel), Kukull, W.A., Lapid, M.I. (Maria I.), Litvan, I., Mackenzie, I.R.A. (Ian), Mendez, M.F. (Mario), Miller, B.L. (Bruce Lars), Onyike, C.U. (Chiadi), Pantelyat, A.Y. (Alexander Y.), Rademakers, S. (Suzanne), Marisa Ramos, E. (Eliana), Roberson, E.D. (Erik D.), Carmela Tartaglia, M. (Maria), Tatton, N.A. (Nadine A.), Toga, A.W. (Arthur), Vetor, A. (Ashley), Weintraub, S. (Sandra), Wong, B. (Bonnie), Wszolek, Z.K. (Zbigniew), Swieten, J.C. (John) van, and Lee, S.E. (Suzee E.)

Abstract

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes

Published
2020
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16. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author

Moore, KM, Nicholas, J, Grossman, M, McMillan, CT, Irwin, DJ, Massimo, L, Van Deerlin, VM, Warren, JD, Fox, NC, Rossor, MN, Mead, S, Bocchetta, M, Boeve, BF, Knopman, DS, Graff-Radford, NR, Forsberg, LK, Rademakers, R, Wszolek, ZK, van Swieten, JC, Jiskoot, LC, Meeter, LH, Dopper, EGP, Papma, JM, Snowden, JS, Saxon, J, Jones, M, Pickering-Brown, S, Le Ber, I, Camuzat, A, Brice, A, Caroppo, P, Ghidoni, R, Pievani, M, Benussi, L, Binetti, G, Dickerson, BC, Lucente, D, Krivensky, S, Graff, C, Oijerstedt, L, Fallstrom, M, Thonberg, H, Ghoshal, N, Morris, JC, Borroni, B, Benussi, A, Padovani, A, Galimberti, D, Scarpini, E, Fumagalli, GG, Mackenzie, IR, Hsiung, G-YR, Sengdy, P, Boxer, AL, Rosen, H, Taylor, JB, Synofzik, M, Wilke, C, Sulzer, P, Hodges, JR, Halliday, G, Kwok, J, Sanchez-Valle, R, Llado, A, Borrego-Ecija, S, Santana, I, Almeida, MR, Tabuas-Pereira, M, Moreno, F, Barandiaran, M, Indakoetxea, B, Levin, J, Danek, A, Rowe, JB, Cope, TE, Otto, M, Anderl-Straub, S, de Mendonca, A, Maruta, C, Masellis, M, Black, SE, Couratier, P, Lautrette, G, Huey, ED, Sorbi, S, Nacmias, B, Laforce, R, Tremblay, M-PL, Vandenberghe, R, Van Damme, P, Rogalski, EJ, Weintraub, S, Gerhard, A, Onyike, CU, Ducharme, S, Papageorgiou, SG, Ng, ASL, Brodtmann, A, Finger, E, Guerreiro, R, Bras, J, Rohrer, JD, Heller, C, Convery, R, Woollacott, IOC, Shafei, R, Graff-Radford, J, Jones, DT, Dheel, CM, Savica, R, Lapid, MI, Baker, M, Fields, JA, Gavrilova, R, Domoto-Reilly, K, Poos, JM, van der Ende, EL, Panman, JL, Kaat, LD, Seelaar, H, Richardson, A, Frisoni, G, Mega, A, Fostinelli, S, Chiang, H-H, Alberici, A, Arighi, A, Fenoglio, C, Heuer, H, Miller, B, Karydas, A, Fong, J, Leitao, MJ, Santiago, B, Duro, D, Ferreira, C, Gabilondo, A, de Arriba, M, Tainta, M, Zulaica, M, Ferreira, CB, Semler, E, Ludolph, A, Landwehrmeyer, B, Volk, AE, Miltenberger, G, Verdelho, A, Afonso, S, Tartaglia, MC, Freedman, M, Rogaeva, E, Ferrari, C, Piaceri, I, Bessi, V, Lombardi, G, St-Onge, F, Dore, M-C, Bruffaerts, R, Vandenbulcke, M, Van den Stock, J, Mesulam, MM, Bigio, E, Koros, C, Papatriantafyllou, J, Kroupis, C, Stefanis, L, Shoesmith, C, Roberson, E, Coppola, G, Ramos, EMDS, Geschwind, D, Moore, KM, Nicholas, J, Grossman, M, McMillan, CT, Irwin, DJ, Massimo, L, Van Deerlin, VM, Warren, JD, Fox, NC, Rossor, MN, Mead, S, Bocchetta, M, Boeve, BF, Knopman, DS, Graff-Radford, NR, Forsberg, LK, Rademakers, R, Wszolek, ZK, van Swieten, JC, Jiskoot, LC, Meeter, LH, Dopper, EGP, Papma, JM, Snowden, JS, Saxon, J, Jones, M, Pickering-Brown, S, Le Ber, I, Camuzat, A, Brice, A, Caroppo, P, Ghidoni, R, Pievani, M, Benussi, L, Binetti, G, Dickerson, BC, Lucente, D, Krivensky, S, Graff, C, Oijerstedt, L, Fallstrom, M, Thonberg, H, Ghoshal, N, Morris, JC, Borroni, B, Benussi, A, Padovani, A, Galimberti, D, Scarpini, E, Fumagalli, GG, Mackenzie, IR, Hsiung, G-YR, Sengdy, P, Boxer, AL, Rosen, H, Taylor, JB, Synofzik, M, Wilke, C, Sulzer, P, Hodges, JR, Halliday, G, Kwok, J, Sanchez-Valle, R, Llado, A, Borrego-Ecija, S, Santana, I, Almeida, MR, Tabuas-Pereira, M, Moreno, F, Barandiaran, M, Indakoetxea, B, Levin, J, Danek, A, Rowe, JB, Cope, TE, Otto, M, Anderl-Straub, S, de Mendonca, A, Maruta, C, Masellis, M, Black, SE, Couratier, P, Lautrette, G, Huey, ED, Sorbi, S, Nacmias, B, Laforce, R, Tremblay, M-PL, Vandenberghe, R, Van Damme, P, Rogalski, EJ, Weintraub, S, Gerhard, A, Onyike, CU, Ducharme, S, Papageorgiou, SG, Ng, ASL, Brodtmann, A, Finger, E, Guerreiro, R, Bras, J, Rohrer, JD, Heller, C, Convery, R, Woollacott, IOC, Shafei, R, Graff-Radford, J, Jones, DT, Dheel, CM, Savica, R, Lapid, MI, Baker, M, Fields, JA, Gavrilova, R, Domoto-Reilly, K, Poos, JM, van der Ende, EL, Panman, JL, Kaat, LD, Seelaar, H, Richardson, A, Frisoni, G, Mega, A, Fostinelli, S, Chiang, H-H, Alberici, A, Arighi, A, Fenoglio, C, Heuer, H, Miller, B, Karydas, A, Fong, J, Leitao, MJ, Santiago, B, Duro, D, Ferreira, C, Gabilondo, A, de Arriba, M, Tainta, M, Zulaica, M, Ferreira, CB, Semler, E, Ludolph, A, Landwehrmeyer, B, Volk, AE, Miltenberger, G, Verdelho, A, Afonso, S, Tartaglia, MC, Freedman, M, Rogaeva, E, Ferrari, C, Piaceri, I, Bessi, V, Lombardi, G, St-Onge, F, Dore, M-C, Bruffaerts, R, Vandenbulcke, M, Van den Stock, J, Mesulam, MM, Bigio, E, Koros, C, Papatriantafyllou, J, Kroupis, C, Stefanis, L, Shoesmith, C, Roberson, E, Coppola, G, Ramos, EMDS, and Geschwind, D

Abstract

BACKGROUND: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. METHODS: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. FINDINGS: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at

Published
2020

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