5th EuropEan MolEcular IMagIng MEEtIng - ESMI

5th EuropEan MolEcular IMagIng MEEtIng – EMIM2010
Serotonergic neurotransmission in early Alzheimer’s disease
Hasselbalch S. G. (1) , Marner L. (1) , Madsen K. (1) , Lehel S. (1) , Barré W. (1) , Knudsen G. M. (1) .
(1) Copenhagen University, Denmark
sgh@nru.dk
Introduction: Post mortem studies suggest involvement
of the serotonin system in Alzheimer’s disease
(AD) and serotonin 2A (5-HT2A) receptors are
globally reduced early in the course of the disease
(1). However, few studies have investigated other
aspects of the serotonergic system, including presynaptic
markers (serotonin transporters, SERT) as
a measure of serotonergic degeneration (2). Further,
recent evidence points to a disease-modifying effect
of 5-HT4 agonism through a decrease in beta-amyloid
load (3). Therefore, we have investigated SERT
and 5-HT4 in early and compared these measures to
the reduction in 5-HT2A receptors.
Methods: For the SERT/5-HT2A comparison, we
included 12 patients (mean age 73.7 ±7.6 years, 8
males) with AD (average MMSE of 24, range 19-26)
and 11 healthy age-matched subjects (mean age 72.5
±6.8 years, 6 males). Subjects were investigated with
a 90 min dynamic [11C]DASB-PET recording to
measure SERT (4) and a 40 min steady-state [18F]
altanserin-PET recording to measure 5-HT2A receptors
(5). In a separate study of 5-HT4 receptors,
the novel radioligand [11C]SB207145 was used in
twelve healthy individuals (mean age 67.2 y, 6 males)
and eleven newly diagnosed AD patients (mean age
70.6 y, 6 males, mean MMSE 24, range 19-27) using
the simplified reference tissue model. Volumes of
interest (VOIs) were delineated automatically on coregistered
3T MRIs, and partial volume correction
was applied to correct for differences in atrophy.
Results: The 5-HT2A receptors were markedly reduced
(25-66%) in AD patients in all regions but
the striatum. Inc contrast, we found a reduction of
SERT binding by 34% (p=0.0003) in the hippocampus,
while most other regions were unaffected.
Midbrain showed no change in binding (p=0.30).
No statistically significant differences in 5-HT4 receptor
binding between healthy individuals and AD patients
were found in any of the included brain regions:
Hippocampus (p = 0.55), posterior cingulate gyrus
(p = 0.22), amygdala (p = 0.77), parietal cortex (p =
0.44), temporal cortex (p = 0.74) and prefrontal cortex
(p = 0.43).
Conclusions: We showed a marked decrease of
5-HT2A binding in patients with mild AD, consistent
with previous findings in MCI (1). The SERT
binding was unaffected by the disease in almost all
cortical regions and in midbrain, suggesting that
the serotonergic innervations and the neuron bodies
in dorsal nucleus raphe are intact, at least early
in the disease. We interpret the SERT reduction in
hippocampus in patients as a decreased serotonergic
innervation, which could be secondary to the neuronal
degeneration taking place in hippocampus of
AD patients. The marked reduction in 5-HT2A may
be related to beta-amyloid accumulation. In contrast
to the 5-HT2A receptor subtype, the 5-HT4 receptor
levels seemed to be unaffected in AD. However,
5-HT4 binding in relation to cognitive function,
neuropsychiatric symptoms and beta-amyloid load
should be further investigated.
Acknowledgement: Supported by The Lundbeck
Foundation, Rigshospitalet, and the Danish Medical
Research Council. The John and Birthe Meyer Foundation
is gratefully acknowledged for the donation
of the Cyclotron and PET-scanner. These studies
were funded in part by the EC - FP6-project DiMI,
LSHB-CT-2005-512146.
References:
1. S. G. Hasselbalch et al., Neurobiol. Aging. 29, 1830
(2008).
2. K. Nielsen et al., Synapse. 59, 270 (2006).
3. S.J. Robert, et al., Neurodegener Dis 5(3-4):163 (2008).
4. M. Ichise et al., J Cereb. Blood Flow Metab. 23, 1096
(2003). L. H. Pinborg et al., J. Cereb. Blood Flow Metab.
23, 985 (2003).
EuropEan SocIEty for MolEcular IMagIng – ESMI
day1
Parallel Session 2: NEUROSCIENCE I