HAI Book 2025 - Flipbook - Page 180
Clarke, Mica
33
Molecular imaging of neurodegeneration – mitochondria, associated
proteins and synapses (MIND-MAPS) in frontotemporal dementia
Mica Clarke1, Alexander Whittington1, Jan Passchier1, Yvonne Lewis1, Luca Passamonti2,
Laigao Chen3, Cristian Salinas4, Hideo Tsukada5, David Cash6, Eugenii Rabiner1, Jonathan
Rohrer6
1
Perceptive, London, GB
Biogen, Boston, MA, US
3
Pfizer, Boston, MA, US
4
Takeda Pharmaceuticals, Boston, MA, US
5
Hamamatsu Photonics, Hamamatsu, JP
6
Dementia Research Centre, UCL Queen Square Institute of Neurology, London, GB
7
MIND-MAPS Consortium, London, GB
2
Mitochondrial and synaptic dysfunction are key features of multiple neurodegenerative disorders. The expression
of synaptic vesicle protein 2A (SV2A) quantified using [11C]UCB-J has been established as an index of expression
of pre-synaptic terminals, while mitochondrial complex I (MC1) has been quantified using [18F]BCPP-EF as a
marker of mitochondrial density. The expression of sigma 1 receptor (S1R) measured using [11C]SA4503 has been
proposed as a marker of mitochondrial-associated membranes (MAMs) connecting mitochondria to the
endoplasmic reticulum. This is the first study to combine the evaluation of these molecular markers in
frontotemporal dementia (FTD).
Ten participants with behavioural variant FTD (age mean 64.2, SD 5.9; disease duration 5.0 years, 5.2; MMSE 22.7,
5.5) and 16 cognitively normal controls (age 63.0, 11.6; MMSE 28.9, 1.1) underwent 90-minute dynamic PET scans
following injection of each of the tracers, with arterial blood collected to generate metabolite-corrected arterial
input function. Five of the FTD group underwent the same procedures 12 months later. Regions of interest (ROIs)
were defined on individual MR images using the CIC anatomical atlas. Regional density was evaluated using the
volume of distribution (VT) corrected for the plasma free fraction (VT/fP) for [11C]SA4503, and the regional VT
normalised to the VT in the centrum semiovale (DVR) for [11C]UCB-J and [18F]BCPP-EF. Group comparisons used
non-parametric Mann-Whitney tests.
Regional density of SV2A, MC1 and S1R was significantly reduced in FTD compared to controls in multiple ROIs
including: frontal, temporal, parietal, insular, anterior cingulate and posterior cingulate cortices and the
hippocampus, amygdala, thalamus, caudate, putamen and cerebellum. The magnitude of the differences between
control and FTD groups is reduced by partial volume correction but not abolished, suggesting reductions are not
entirely driven by atrophy. Follow up data revealed further reductions in MC1 and SV2A. Longitudinal investigation
of these molecular changes requires replication in a larger cohort.
HAI2025 - 180
