Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: a longitudinal arterial spin labeling study
Open accessAbstract
OBJECTIVE: Frontotemporal dementia (FTD) is characterized by behavioral disturbances and language problems. Familial forms can be caused by genetic defects in microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72. In light of upcoming clinical trials with potential disease-modifying agents, the development of sensitive biomarkers to evaluate such agents in the earliest stage of FTD is crucial. In the current longitudinal study we used arterial spin labeling MRI (ASL) in presymptomatic carriers of MAPT and GRN mutations to investigate early changes in cerebral blood flow (CBF). METHODS: Healthy first-degree relatives of patients with a MAPT or GRN mutation underwent ASL at baseline and follow-up after two years. We investigated cross-sectional and longitudinal differences in CBF between mutation carriers (n = 34) and controls without a mutation (n = 31). RESULTS: GRN mutation carriers showed significant frontoparietal hypoperfusion compared with controls at follow-up, whereas we found no cross-sectional group differences in the total study group or the MAPT subgroup. Longitudinal analyses revealed a significantly stronger decrease in CBF in frontal, temporal, parietal, and subcortical areas in the total group of mutation carriers and the GRN subgroup, with the strongest decrease in two mutation carriers who converted to clinical FTD during follow-up. INTERPRETATION: We demonstrated longitudinal alterations in CBF in presymptomatic FTD independent of grey matter atrophy, with the strongest decrease in individuals that developed symptoms during follow-up. Therefore, ASL could have the potential to serve as a sensitive biomarker of disease progression in the presymptomatic stage of FTD in future clinical trials.
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A genetic ASL study in FTD patients showed that a specific pattern of frontal, temporal, parietal and subcortical CBF decrease accompanied clinical conversion from pre-symptomatic to symptomatic stages in MAPT and GRN mutation carriers over 2 years.
“A genetic study on arterial spin labelling (ASL) in FTD patients, measuring cerebral blood flow (CBF), showed that a specific pattern of frontal, temporal, parietal and subcortical CBF decrease accompanied the clinical conversion from pre-symptomatic to symptomatic stages in MAPT and GRN mutation carriers over 2 years (Dopper et al., 2016).”
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 Dopper et al., 2016
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- Authors
- Dopper, E. G. P., Chalos, V., Ghariq, E., den Heijer, T., Hafkemeijer, A., Jiskoot, L. C., de Koning, I., Seelaar, H., van Minkelen, R., van Osch, M. J. P., Rombouts, S. A. R. B., & van Swieten, J. C.
- Affiliations
- Leiden University Medical Center (NL)
- Erasmus MC (NL)
- Leiden University (NL)
- ORCID
- Venue
- NeuroImage: Clinical
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 12
- Pages
- 460-465
- ISSN
- 2213-1582 (ISSN-L)
- PMC
- PMC5011170
- OpenAlex
- W2506919437
- Cited by
- 57
- References
- 56
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 8 · 2021: 8 · 2020: 11 · 2019: 4 · 2018: 6 · 2017: 5
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- NeuroImage Clinical (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Dioraphte Foundation (09-02-03-00)
- NWO (HCMI 056-13-018, 016130677, 05613010)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- frontotemporal dementia, presymptomatic mutation carriers, MAPT mutations, GRN mutations, cerebral blood flow, arterial spin labeling, disease biomarkers, disease progression, familial frontotemporal dementia
- MeSH terms
- Progranulins, Adult, Aged, Cerebrovascular Circulation, Cross-Sectional Studies, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Neuropsychological Tests, Spin Labels, Statistics as Topic, tau Proteins, Intercellular Signaling Peptides and Proteins, Young Adult, Frontotemporal Dementia
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