Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: A longitudinal arterial spin labeling study.
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).



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).



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.



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.
Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Neurology, VU Medical Center, Amsterdam, The Netherlands.
Elise G P
EG
Dopper
Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
Vicky
V
Chalos
C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
Eidrees
E
Ghariq
Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Neurology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands.
Tom
T
den Heijer
Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Methodology and Statistics, Institute of Psychology, Leiden University, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands.
Anne
A
Hafkemeijer
Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Neuropsychology, Erasmus Medical Center, Rotterdam, The Netherlands.
Lize C
LC
Jiskoot
Department of Neuropsychology, Erasmus Medical Center, Rotterdam, The Netherlands.
Inge
I
de Koning
Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
Harro
H
Seelaar
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Rick
R
van Minkelen
C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
Matthias J P
MJ
van Osch
Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Methodology and Statistics, Institute of Psychology, Leiden University, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands.
Serge A R B
SA
Rombouts
Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands.
John C
JC
van Swieten
D000328:Adult; D000368:Aged; D002560:Cerebrovascular Circulation / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000000981:diagnostic imaging / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D000077153:Progranulins; D013113:Spin Labels; D013223:Statistics as Topic; D055815:Young Adult; D016875:tau Proteins / Q000235:genetics*
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D013113:Spin Labels; D016875:tau Proteins
AD, Alzheimer's disease; ASL, arterial spin labeling; Arterial spin labeling; BDI-II, Beck Depression inventory II (BDI-II); BNT, Boston Naming Test; CBF, cerebral blood flow; Cerebral blood flow; FDG-PET, positron emission tomography with 18F-fluorodeoxyglucose; FTD, frontotemporal dementia; Frontotemporal dementia; GRN, progranulin; LDST, Letter Digit Substitution Test; MAPT, microtubule-associated protein tau; MMSE, Mini-Mental State Examination; Presymptomatic; RAVLT, Rey Auditory Verbal Learning Test; SAT, Semantic Association Test; TMT, Trailmaking Test; VAT, Visual Association Test; WCST, Wisconsin Card Sorting Test