Development of disease-modifying drugs for frontotemporal dementia spectrum disorders

Panza, Francesco; Lozupone, Madia; Seripa, Davide; Daniele, Antonio; Watling, Mark; Giannelli, Gianluigi; Imbimbo, Bruno P.

doi:10.1038/s41582-020-0330-x

Cited by 122Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Development of disease-modifying drugs for frontotemporal dementia spectrum disorders

Panza, Francesco, Lozupone, Madia, Seripa, Davide, Daniele, Antonio, Watling, Mark, Giannelli, Gianluigi, Imbimbo, Bruno P.·2020·Nature Reviews Neurology

DOI 10.1038/s41582-020-0330-x

Open this paper in CoChat — free account

Abstract

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Currently available treatments are symptomatic and provide limited benefit. However, the increased understanding of FTD pathogenesis is driving the development of potential disease-modifying therapies. Most of these drugs target pathological tau - this category includes tau phosphorylation inhibitors, tau aggregation inhibitors, active and passive anti-tau immunotherapies, and MAPT-targeted antisense oligonucleotides. Some of these therapeutic approaches are being tested in phase II clinical trials. Pharmacological approaches that target the effects of GRN and C9orf72 mutations are also in development. Key results of large clinical trials will be available in a few years. However, clinical trials in FTD pose several challenges, and the development of specific brain imaging and molecular biomarkers could facilitate the recruitment of clinically homogenous groups to improve the chances of positive clinical trial results.

Integrity signals

Registry

Crossref · 10.1038/s41582-020-0330-x

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

It is estimated that 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN, or MAPT genes.
“It is estimated that 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN, or MAPT genes.316”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [316]

NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.02.018 · Cited by 10,537 · see citing works
Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.011 · Cited by 4,936 · 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
Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents
Goldman, L. S. (1998) · JAMA · doi:10.1001/jama.279.14.1100 · Cited by 1,082 · see citing works
Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria
Strong, M. J., Abrahams, S., Goldstein, L. H., Woolley, S., Mclaughlin, P., Snowden, J., Mioshi, E., Roberts-South, A., Benatar, M., HortobáGyi, T., et al. (2017) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2016.1267768 · Cited by 909 · see citing works
Phosphorylation affects the ability of tau protein to promote microtubule assembly.
Lindwall, G., & Cole, R. D. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42989-9 · Cited by 901 · see citing works
Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia
Skibinski, G., Parkinson, N. J., Brown, J. M., Chakrabarti, L., Lloyd, S. L., Hummerich, H., Nielsen, J. E., Hodges, J. R., Spillantini, M. G., Thusgaard, T., et al. (2005) · Nature Genetics · doi:10.1038/ng1609 · Cited by 822 · see citing works
O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease
Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G. W., & Gong, C.-X. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400348101 · Cited by 775 · see citing works
Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy
DeVos, S. L., Miller, R. L., Schoch, K. M., Holmes, B. B., Kebodeaux, C. S., Wegener, A. J., Chen, G., Shen, T., Tran, H., Nichols, B., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aag0481 · Cited by 516 · see citing works
Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits
Min, S.-W., Chen, X., Tracy, T. E., Li, Y., Zhou, Y., Wang, C., Shirakawa, K., Minami, S. S., Defensor, E., Mok, S. A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3951 · Cited by 516 · see citing works
Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial
Gauthier, S., Feldman, H. H., Schneider, L. S., Wilcock, G. K., Frisoni, G. B., Hardlund, J. H., Moebius, H. J., Bentham, P., Kook, K. A., Wischik, D. J., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31275-2 · Cited by 427 · see citing works
Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis
Kraemer, B. C., Schuck, T., Wheeler, J. M., Robinson, L. C., Trojanowski, J. Q., Lee, V. M. Y., & Schellenberg, G. D. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0659-0 · Cited by 350 · see citing works
A phase 2 trial of the GSK‐3 inhibitor tideglusib in progressive supranuclear palsy
Tolosa, E., Litvan, I., Höglinger, G. U., Burn, D., Lees, A., Andrés, M. V., Gómez‐Carrillo, B., León, T., del Ser, T., & for the TAUROS Investigators (2014) · Movement Disorders · doi:10.1002/mds.25824 · Cited by 320 · see citing works
Hsp90-Tau complex reveals molecular basis for specificity in chaperone action
Karagöz, G. E., Duarte, A. M. S., Akoury, E., Ippel, H., Biernat, J., Morán Luengo, T., Radli, M., Didenko, T., Nordhues, B. A., Veprintsev, D. B., et al. (2014) · Cell · doi:10.1016/j.cell.2014.01.037 · Cited by 318 · see citing works
Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease
Pottier, C., Bieniek, K. F., Finch, N., van de Vorst, M., Baker, M., Perkersen, R., Brown, P., Ravenscroft, T., van Blitterswijk, M., Nicholson, A. M., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1436-x · Cited by 312 · see citing works
A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia
Huey, E. D., Putnam, K. T., & Grafman, J. (2006) · Neurology · doi:10.1212/01.wnl.0000191304.55196.4d · Cited by 299 · see citing works
Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial
Boxer, A. L., Lang, A. E., Grossman, M., Knopman, D. S., Miller, B. L., Schneider, L. S., Doody, R. S., Lees, A., Golbe, L. I., Williams, D. R., et al. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70088-2 · Cited by 294 · see citing works
Preliminary Findings: Behavioral Worsening on Donepezil in Patients With Frontotemporal Dementia
Mendez, M. F., Shapira, J. S., McMurtray, A., & Licht, E. (2007) · The American Journal of Geriatric Psychiatry · doi:10.1097/01.jgp.0000231744.69631.33 · Cited by 267 · see citing works
Human secreted tau increases amyloid-beta production
Bright, J., Hussain, S., Dang, V., Wright, S., Cooper, B., Byun, T., Ramos, C., Singh, A., Parry, G., Stagliano, N., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.09.007 · Cited by 230 · see citing works
Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial
Boxer, A. L., Knopman, D. S., Kaufer, D. I., Grossman, M., Onyike, C., Graf-Radford, N., Mendez, M., Kerwin, D., Lerner, A., Wu, C.-K., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70320-4 · Cited by 228 · see citing works
Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice.
Ozcelik, S., Fraser, G., Castets, P., Schaeffer, V., Skachokova, Z., Breu, K., Clavaguera, F., Sinnreich, M., Kappos, L., Goedert, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062459 · Cited by 226 · see citing works
Activity-Dependent Neuroprotective Protein Snippet NAP Reduces Tau Hyperphosphorylation and Enhances Learning in a Novel Transgenic Mouse Model
Vulih-Shultzman, I., Pinhasov, A., Mandel, S., Grigoriadis, N., Touloumi, O., Pittel, Z., & Gozes, I. (2007) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.129551 · Cited by 219 · see citing works
Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target
Holmes, B. B., & Diamond, M. I. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.549295 · Cited by 202 · see citing works
Frontotemporal dementia and related disorders: Deciphering the enigma
Josephs, K. A. (2008) · Annals of Neurology · doi:10.1002/ana.21426 · Cited by 166 · see citing works
Degradation of tau protein by autophagy and proteasomal pathways
Wang, Y., & Mandelkow, E. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120071 · Cited by 166 · see citing works
Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice
Hastings, N. B., Wang, X., Song, L., Butts, B. D., Grotz, D., Hargreaves, R., Fred Hess, J., Hong, K.-L. K., Huang, C. R.-R., Hyde, L., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0181-0 · Cited by 164 · see citing works
Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial
Höglinger, G. U., Huppertz, H., Wagenpfeil, S., Andrés, M. V., Belloch, V., León, T., del Ser, T., & for the TAUROS MRI Investigators (2014) · Movement Disorders · doi:10.1002/mds.25815 · Cited by 161 · see citing works
Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum
Meeter, L. H. H., Vijverberg, E. G., Del Campo, M., Rozemuller, A. J. M., Donker Kaat, L., de Jong, F. J., van der Flier, W. M., Teunissen, C. E., van Swieten, J. C., & Pijnenburg, Y. A. L. (2018) · Neurology · doi:10.1212/wnl.0000000000005261 · Cited by 122 · see citing works
CSF neurofilament proteins in the differential diagnosis of dementia
de Jong, D., Jansen, R. W. M. M., Pijnenburg, Y. A. L., van Geel, W. J. A., Borm, G. F., Kremer, H. P. H., & Verbeek, M. M. (2007) · Journal of Neurology, Neurosurgery &amp; Psychiatry · doi:10.1136/jnnp.2006.107326 · Cited by 120 · see citing works
Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases
Sergeant, N., David, J.-P., Lefranc, D., Vermersch, P., Wattez, A., & Delacourte, A. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00859-4 · Cited by 117 · see citing works
A Double-Blind, Placebo-Controlled, Ascending-Dose, Randomized Study to Evaluate the Safety, Tolerability and Effects on Cognition of AL-108 after 12 Weeks of Intranasal Administration in Subjects with Mild Cognitive Impairment
Morimoto, B. H., Schmechel, D., Hirman, J., Blackwell, A., Keith, J., Gold, M., & on behalf of the AL-108-211 Study Investigators (2013) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000348347 · Cited by 115 · see citing works
Proteomics Approaches for Biomarker and Drug Target Discovery in ALS and FTD
Hedl, T. J., San Gil, R., Cheng, F., Rayner, S. L., Davidson, J. M., De Luca, A., Villalva, M. D., Ecroyd, H., Walker, A. K., & Lee, A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00548 · Cited by 87 · see citing works
Tau-directed approaches for the treatment of Alzheimer’s disease: focus on leuco-methylthioninium
Seripa, D., Solfrizzi, V., Imbimbo, B. P., Daniele, A., Santamato, A., Lozupone, M., Zuliani, G., Greco, A., Logroscino, G., & Panza, F. (2016) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2016.1140039 · Cited by 50 · see citing works
Self-citation
Assessment of CSF Aβ42 as an aid to discriminating Alzheimer's disease from other dementias and mild cognitive impairment: A meta-analysis of 50 studies
Tang, W., Huang, Q., Wang, Y., Wang, Z.-Y., & Yao, Y.-Y. (2014) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2014.07.015 · Cited by 38 · see citing works

Flagged first, then by citations

Sorted by citations

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616 · see citing works
Tauopathies: new perspectives and challenges
Zhang, Y., Wu, K.-M., Yang, L., Dong, Q., & Yu, J.-T. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00533-z · Cited by 323 · see citing works
Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries
Logroscino, G., Piccininni, M., Graff, C., Hardiman, O., Ludolph, A. C., Moreno, F., Otto, M., Remes, A. M., Rowe, J. B., Seelaar, H., et al. (2023) · JAMA Neurology · doi:10.1001/jamaneurol.2022.5128 · Cited by 91 · see citing works
Anti-amyloid-β protein agents for the treatment of Alzheimer’s disease: an update on emerging drugs
Lozupone, M., Solfrizzi, V., D’Urso, F., Di Gioia, I., Sardone, R., Dibello, V., Stallone, R., Liguori, A., Ciritella, C., Daniele, A., et al. (2020) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2020.1808621 · Cited by 77 · see citing works
Self-citation
Pharmacotherapy for Neuropsychiatric Symptoms in Frontotemporal Dementia
Le, C., & Finger, E. (2021) · CNS Drugs · doi:10.1007/s40263-021-00854-5 · Cited by 26 · see citing works
Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies
Panza, F., Dibello, V., Sardone, R., Castellana, F., Zupo, R., Lampignano, L., Bortone, I., Stallone, R., Cirillo, N., Damiani, C., et al. (2023) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2023.2233892 · Cited by 22 · see citing works
Self-citation
Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI
Ma, D., Stocks, J., Rosen, H., Kantarci, K., Lockhart, S. N., Bateman, J. R., Craft, S., Gurcan, M. N., Popuri, K., Beg, M. F., et al. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1331677 · Cited by 9 · see citing works

Authors: Panza, F., Lozupone, M., Seripa, D., Daniele, A., Watling, M., Giannelli, G., & Imbimbo, B. P.
Affiliations: Gastroenterology Hospital "Saverio de Bellis" (IT)
University of Bari Aldo Moro (IT)
Casa Sollievo della Sofferenza (IT)
Università Cattolica del Sacro Cuore (IT)
Chiesi (Italy) (IT)
Corresponding author: Panza, Francesco
ORCID: Panza, Francesco
Lozupone, Madia
Seripa, Davide
Daniele, Antonio
Watling, Mark
Giannelli, Gianluigi
Imbimbo, Bruno P.
Venue: Nature Reviews Neurology
Publisher: Springer Science and Business Media LLC
Published: 2020-03-23
Volume: 16
Issue: 4
Pages: 213-228
ISSN: 1759-4758 (ISSN-L)
1759-4766
DOI: 10.1038/s41582-020-0330-x
OpenAlex: W3012639103
Cited by: 122
References: 34
Citations by year: 2026: 7 · 2025: 13 · 2024: 21 · 2023: 18 · 2022: 30 · 2021: 24 · 2020: 9
FWCI: 2.30
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Neurology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: frontotemporal dementia, disease-modifying therapy, tau protein, TDP-43, C9orf72, gene regulatory networks, MAPT, tau aggregation inhibitors, antisense oligonucleotides, clinical trial design, biomarkers, neuroimaging
MeSH terms: C9orf72 Protein, Drug Development, Progranulins, Amyotrophic Lateral Sclerosis, Antibodies, DNA-Binding Proteins, Humans, Immunization, Passive, Supranuclear Palsy, Progressive, Immunotherapy, Active, tau Proteins, Aphasia, Primary Progressive, RNA-Binding Protein FUS, RNA-Binding Protein EWS, TATA-Binding Protein Associated Factors, Tubulin Modulators, Frontotemporal Dementia, Molecular Targeted Therapy

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

Development of disease-modifying drugs for frontotemporal dementia spectrum disorders

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Record

About these checks