Distinct early symptoms in neuropathologically proven frontotemporal lobar degeneration
Abstract
Objectives: Frontotemporal lobar degeneration (FTLD) is associated with accumulation of neurodegeneration‐related protein, such as tau, TAR DNA‐binding protein 43 (TDP‐43), or fused in sarcoma protein (FUS). There have been very few systematic studies of the early symptoms of clinical phenotypes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA). Clinical subtypes and the patterns of atrophy reflect protein‐accumulation patterns, but the relationship between early symptoms and pathological findings remains unclear. Methods: We retrospectively investigated the clinical records and examined the neuropathology of 39 bvFTD and 6 svPPA patients to identify symptoms appearing within 2 years of the first clinically apparent changes. Results: The bvFTD group consisted of 13 FTLD‐tau, 18 FTLD‐TDP, and 8 FTLD‐FUS, and the svPPA group consisted of 6 FTLD‐TDP. Age at death is significantly younger in FTLD‐FUS (52.8 ± 12.6; P = 0.0104 < 0.05). Over 50% of bvFTD patients show apathy or inertia, and distinct language features appear early in svPPA. Interestingly, bvFTD and svPPA frequently present additional symptoms, not included in the diagnostic criteria, such as physical signs, reticence, dazed condition, and delusions. Stereotyped behaviors, hyperorality and dietary changes are prominent in FTLD‐FUS, while linguistic deficits are greater in FTLD‐TDP. Conclusions: Specific symptoms tend to appear in the early stage of FTLD in each pathological background. They might reflect the morphological features and pathological progression, and should be helpful in the stratification of patients for future therapeutic trials based on the proteinopathies.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Pathology-specific profiles point to impaired visual construction in tau-positive FTLD and confrontation naming in tau-negative FTLD, and linguistic deficits in FTLD-TDP.
“Pathology-specific profiles point to impaired visual construction in tau-positive FTLD and confrontation naming in tau-negative FTLD, and linguistic deficits in FTLD-TDP (Grossman et al., 2008; Kawakami et al., 2021).”
From The pursuit for markers of disease progression in behavioral variant frontotemporal dementia: a scoping review to optimize outcome measures for clinical trials (2024) · cites this paper as Kawakami et al., 2021
Cites
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975) · Journal of Psychiatric Research · doi:10.1016/0022-3956(75)90026-6 · Cited by 88,282 · see citing works
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576 · see citing works
Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia
Rascovsky, K., Hodges, J. R., Knopman, D., Mendez, M. F., Kramer, J. H., Neuhaus, J., van Swieten, J. C., Seelaar, H., Dopper, E. G. P., Onyike, C. U., et al. (2011) · Brain · doi:10.1093/brain/awr179 · Cited by 5,221 · see citing works
Classification of primary progressive aphasia and its variants
Gorno-Tempini, M. L., Hillis, A. E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S. F., Ogar, J. M., Rohrer, J. D., Black, S., Boeve, B. F., et al. (2011) · Neurology · doi:10.1212/wnl.0b013e31821103e6 · Cited by 5,141 · see citing works
Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria
Neary, D., Snowden, J. S., Gustafson, L., Passant, U., Stuss, D., Black, S., Freedman, M., Kertesz, A., Robert, P. H., Albert, M., et al. (1998) · Neurology · doi:10.1212/wnl.51.6.1546 · Cited by 5,047 · see citing works
Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., et al. (1998) · Nature · doi:10.1038/31508 · Cited by 3,498 · see citing works
Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.10.093 · Cited by 2,732 · see citing works
Self-citationMackenzie, I. R. A., Neumann, M., Bigio, E. H., Cairns, N. J., Alafuzoff, I., Kril, J., Kovacs, G. G., Ghetti, B., Halliday, G., Holm, I. E., et al. (2010) · Acta Neuropathologica · doi:10.1007/s00401-009-0612-2 · Cited by 1,012 · see citing works
A new subtype of frontotemporal lobar degeneration with FUS pathology
Neumann, M., Rademakers, R., Roeber, S., Baker, M., Kretzschmar, H. A., & Mackenzie, I. R. A. (2009) · Brain · doi:10.1093/brain/awp214 · Cited by 722 · see citing works
Distinct behavioural profiles in frontotemporal dementia and semantic dementia
Snowden, J., Bathgate, D., Varma, A., Blackshaw, A., Gibbons, Z. C., & Neary, D. (2001) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.70.3.323 · Cited by 604 · see citing works
Neuropathological background of phenotypical variability in frontotemporal dementia
Josephs, K. A., Hodges, J. R., Snowden, J. S., Mackenzie, I. R., Neumann, M., Mann, D. M. A., & Dickson, D. W. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0839-6 · Cited by 453 · see citing works
Mackenzie, I. R., Neumann, M., Bigio, E. H., Cairns, N. J., Alafuzoff, I. I., Kril, J. J., Kovács, G. G., Ghetti, B. F., Halliday, G. M., Holm, I. E., et al. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0460-5 · Cited by 418 · see citing works
Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria
Faber, R., & Neary, D. (1999) · Neurology · doi:10.1212/wnl.53.5.1158-b · Cited by 371 · see citing works
Early frontotemporal dementia targets neurons unique to apes and humans
Seeley, W. W., Carlin, D. A., Allman, J. M., Macedo, M. N., Bush, C., Miller, B. L., & DeArmond, S. J. (2006) · Annals of Neurology · doi:10.1002/ana.21055 · Cited by 364 · see citing works
Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration
Rohrer, J. D., Lashley, T., Schott, J. M., Warren, J. D., Mead, S., Isaacs, A. M., Beck, J. A., Hardy, J., de Silva, R., Warrington, E. K., et al. (2011) · Brain · doi:10.1093/brain/awr198 · Cited by 359 · see citing works
Whitwell, J. L., Przybelski, S. A., Weigand, S. D., Ivnik, R. J., Vemuri, P., Gunter, J. L., Senjem, M. L., Shiung, M. M., Boeve, B. F., Knopman, D. S., et al. (2009) · Brain · doi:10.1093/brain/awp232 · Cited by 306 · see citing works
Apathy and disinhibition in frontotemporal dementia
Zamboni, G., Huey, E., Krueger, F., Nichelli, P., & Grafman, J. (2008) · Neurology · doi:10.1212/01.wnl.0000324920.96835.95 · Cited by 282 · see citing works
Imai, Y., & Hasegawa, K. (1994) · Hong Kong journal of psychiatry · Cited by 249 · see citing works
Selective functional, regional, and neuronal vulnerability in frontotemporal dementia
Seeley, W. W. (2008) · Current Opinion in Neurology · doi:10.1097/wco.0b013e3283168e2d · Cited by 235 · see citing works
Cognitive profiles differ in autopsy-confirmed frontotemporal dementia and AD
Rascovsky, K., Salmon, D. P., Ho, G. J., Galasko, D. R., Peavy, G. M., Hansen, L. A., & Thal, L. J. (2002) · Neurology · doi:10.1212/wnl.58.12.1801 · Cited by 197 · see citing works
Orbitofrontal Dysfunction Related to Both Apathy and Disinhibition in Frontotemporal Dementia
Peters, F., Perani, D., Herholz, K., Holthoff‐Detto, V., Beuthien‐Baumann, B., Sorbi, S., Pupi, A., Degueldre, C., Lemaire, C. F., Collette, F., et al. (2006) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000091898 · Cited by 190 · see citing works
Hutchinson, A. D., & Mathias, J. L. (2007) · Journal of Neurology, Neurosurgery &amp; Psychiatry · doi:10.1136/jnnp.2006.100669 · Cited by 187 · see citing works
Velakoulis, D., Walterfang, M., Mocellin, R., Pantelis, C., & McLean, C. (2009) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.108.057034 · Cited by 179 · see citing works
The incidence of frontotemporal lobar degeneration in Rochester, Minnesota, 1990 through 1994
Knopman, D. S., Petersen, R. C., Edland, S. D., Cha, R. H., & Rocca, W. A. (2004) · Neurology · doi:10.1212/01.wnl.0000106827.39764.7e · Cited by 173 · see citing works
Frontotemporal Dementia Associated With the<i>C9ORF72</i>Mutation: A Unique Clinical Profile
Devenney, E., Hornberger, M., Irish, M., Mioshi, E., Burrell, J., Tan, R., Kiernan, M. C., & Hodges, J. R. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6002 · Cited by 167 · see citing works
Snowden, J. S., Hu, Q., Rollinson, S. J., Halliwell, N. A., Robinson, A., Davidson, Y. S., Momeni, P., Baborie, A., Griffiths, T. D., Jaros, E., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0816-0 · Cited by 131 · see citing works
The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
Kawakami, I., Arai, T., & Hasegawa, M. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02077-x · Cited by 128 · see citing works
Self-citationLandin-Romero, R., Kumfor, F., Leyton, C. E., Irish, M., Hodges, J. R., & Piguet, O. (2017) · NeuroImage · doi:10.1016/j.neuroimage.2016.03.032 · Cited by 116 · see citing works
Kersaitis, C., Halliday, G. M., & Kril, J. J. (2004) · Acta Neuropathologica · doi:10.1007/s00401-004-0917-0 · Cited by 113 · see citing works
Yokota, O., Tsuchiya, K., Arai, T., Yagishita, S., Matsubara, O., Mochizuki, A., Tamaoka, A., Kawamura, M., Yoshida, H., Terada, S., et al. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0493-4 · Cited by 90 · see citing works
Self-citationPsychosis in Frontotemporal Dementia
Shinagawa, S., Nakajima, S., Plitman, E., Graff‐Guerrero, A., Mimura, M., Nakayama, K., & Miller, B. L. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140312 · Cited by 79 · see citing works
Self-citationInitial Symptoms in Frontotemporal Dementia and Semantic Dementia Compared with Alzheimer’s Disease
Shinagawa, S., Ikeda, M., Fukuhara, R., & Tanabe, H. (2005) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000090139 · Cited by 74 · see citing works
Self-citationProgress and Challenges in Frontotemporal Dementia Research: A 20-Year Review
Hodges, J., & Piguet, O. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-171087 · Cited by 55 · see citing works
Review: Fluid biomarkers for frontotemporal dementias
Zetterberg, H., van Swieten, J. C., Boxer, A. L., & Rohrer, J. D. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12530 · Cited by 48 · see citing works
The Relationship Between Schizophrenia and Frontotemporal Dementia
Cooper, J. J., & Ovsiew, F. (2013) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988713490992 · Cited by 40 · see citing works
Current and Emerging Pharmacological Targets for the Treatment of Alzheimer’s Disease
Morsy, A., & Trippier, P. C. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190744 · Cited by 34 · see citing works
Cieślak, A., Smith, E. E., Lysack, J. T., Ismail, Z., & Mortby, M. E. (2017) · International Psychogeriatrics · doi:10.1017/s1041610217001855 · Cited by 31 · see citing works
Hyperorality in Epileptic Seizures: Periictal Incomplete Klüver–Bucy Syndrome
Janszky, J., Fogarasi, A., Magalova, V., Tuxhorn, I., & Ebner, A. (2005) · Epilepsia · doi:10.1111/j.1528-1167.2005.69404.x · Cited by 27 · see citing works
Family history of frontotemporal lobar degeneration in Asia – an international multi-center research
Fukuhara, R., Ghosh, A., Fuh, J., et al. (2014) · International Psychogeriatrics · doi:10.1017/s1041610214000635 · Cited by 20 · see citing works
Neuropsychological Testing in Pathologically Verified Alzheimer Disease and Frontotemporal Dementia
Ritter, A. R., Léger, G. C., Miller, J. B., & Banks, S. J. (2016) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000181 · Cited by 20 · see citing works
Somatic complaints in frontotemporal dementia.
Waldö, M. L., Santillo, A. F., Gustafson, L., Englund, E. M., & Passant, U. (2014) · Europe PMC (PubMed Central) · Cited by 19 · see citing works
Ishiura, H., & Tsuji, S. (2015) · Journal of Neurogenetics · doi:10.3109/01677063.2015.1085980 · Cited by 18 · see citing works
Kawakami, I., Kobayashi, Z., Arai, T., Yokota, O., Nonaka, T., Aoki, N., Niizato, K., Oshima, K., Higashi, S., Katsuse, O., et al. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0304-9 · Cited by 10 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Fieldhouse, J. L. P., van Paassen, D. N., van Engelen, M.-P. E., De Boer, S. C. M., Hartog, W. L., Braak, S., Schoonmade, L. J., Schouws, S. N. T. M., Krudop, W. A., Oudega, M. L., et al. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1382593 · Cited by 8 · see citing works
- Authors
- Kawakami, I., Arai, T., Shinagawa, S., Niizato, K., Oshima, K., & Ikeda, M.
- Affiliations
- Tokyo Metropolitan Matsuzawa Hospital (JP)
- University of Tsukuba (JP)
- Jikei University School of Medicine (JP)
- The University of Osaka (JP)
- Corresponding author
- Kawakami, Ito
- Venue
- International Journal of Geriatric Psychiatry
- Publisher
- Wiley
- Published
- 2020-08-26
- Volume
- 36
- Issue
- 1
- Pages
- 38-45
- ISSN
- 0885-6230 (ISSN-L)
- 1099-1166
- OpenAlex
- W3047179533
- Cited by
- 7
- References
- 43
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Geriatric Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Agency for Medical Research and Development (JP18dm0908001)
- Naito Foundation (Naito Foundation Subsidy for Female Researchers)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- frontotemporal lobar degeneration, behavioral variant frontotemporal dementia, semantic dementia, FTLD-tau, FTLD-TDP, early symptoms, apathy, stereotypy, hyperorality, language deficits, delusions, reticence, proteinopathies, age at death
- MeSH terms
- DNA-Binding Proteins, Humans, Phenotype, Retrospective Studies, tau Proteins, RNA-Binding Protein FUS, Frontotemporal Lobar Degeneration, Frontotemporal Dementia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review