In vivo detection of neuropathologic changes in presymptomatic MAPT mutation carriers: a PET and MRI study.
BACKGROUND
Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies.


METHODS
We investigated microglial activation with [(11)C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with l-[beta-(11)C]dopa PET, acetylcholinesterase (AChE) activity with [(11)C]N-methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38-41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [(11)C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with l-[beta-(11)C]dopa and [(11)C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons.


RESULTS
Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs.


CONCLUSIONS
Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality.
Miyoshi
Michie
M
Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
Shinotoh
Hitoshi
H
Wszolek
Zbigniew K
ZK
Strongosky
Audrey J
AJ
Shimada
Hitoshi
H
Arakawa
Ryosuke
R
Higuchi
Makoto
M
Ikoma
Yoko
Y
Yasuno
Fumihiko
F
Fukushi
Kiyoshi
K
Irie
Toshiaki
T
Ito
Hiroshi
H
Suhara
Tetsuya
T
D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D057180:Frontotemporal Dementia / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009154:Mutation; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D016875:tau Proteins / Q000235:genetics*
C054369:MAPT protein, human; D016875:tau Proteins