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Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review
Open accessAbstract
Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future.
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“These brain regions have been previously shown to be susceptible to age-related neurodegenerative diseases.”
From Molecular and spatial signatures of mouse brain aging at single-cell resolution (2023) · cites this paper as [33]
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“However, there are several different pathological proteins and aggregation morphologies in FTD, with generally weak correlations between clinical syndrome and the type of pathological protein (Seelaar et al., 2011)”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Seelaar et al., 2011
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“However, there are several different pathological proteins and aggregation morphologies in FTD, with generally weak correlations between clinical syndrome and the type of pathological protein (Seelaar et al., 2011)”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Seelaar et al., 2011
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From rare to common and back again: 60years of lysosomal dysfunction
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“…with ALS or FTLD-TDP type B were included in the Irwin study [42], they were excluded from our study given that TDP-43 type B is associated with FTD-ALS phenotypes [35], and participants with ALS have significantly higher plasma NfL than participants with FTD, which may confound our analyses [5].”
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Phase 1 study of latozinemab in progranulin‐associated frontotemporal dementia
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Altered Expression of Circulating Cdc42 in Frontotemporal Lobar Degeneration
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Self-citationProgressive Supranuclear Palsy and Corticobasal Syndrome
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microRNA‐based predictor for diagnosis of frontotemporal dementia
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Self-citationTargeting Progranulin as an Immuno-Neurology Therapeutic Approach
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Metadata
- Authors
- Seelaar, H., Rohrer, J. D., Pijnenburg, Y. A. L., Fox, N. C., & van Swieten, J. C.
- Affiliations
- Erasmus MC (NL)
- National Hospital for Neurology and Neurosurgery (GB)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2010-10-22
- Volume
- 82
- Issue
- 5
- Pages
- 476-486
- ISSN
- 0022-3050 (ISSN-L)
- OpenAlex
- W2102932082
- Cited by
- 609
- References
- 222
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 39 · 2023: 23 · 2022: 35 · 2021: 33 · 2020: 44 · 2019: 42 · 2018: 34 · 2017: 31 · 2016: 49 · 2015: 41 · 2014: 45 · 2013: 65 · 2012: 54
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- HAL (submittedVersion, other-oa)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Alzheimer's Research Trust
- National Institute for Health and Care Research (NF-SI-0508-10123)
- Hersenstichting
- Stichting Dioraphte
- Medical Research Council
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- frontotemporal dementia, frontotemporal lobar degeneration, semantic dementia, progressive nonfluent aphasia, tauopathy, TDP-43, FUS, progranulin, tau protein, VCP, CHMP2B, amyotrophic lateral sclerosis, neuroimaging, brain atrophy, neuropsychological assessment, disease progression, early diagnosis, genetic heterogeneity
- MeSH terms
- Progranulins, Brain, Cognition, Humans, Magnetic Resonance Imaging, Risk Factors, Social Perception, Biomarkers, tau Proteins, Intercellular Signaling Peptides and Proteins, Executive Function, Frontotemporal Dementia
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