Book of abstracts - British Neuroscience Association

69.02
Effects of AB42 deposition in Alzheimer`s APPxPS1 mice:
inflammatory response and regional MRI volumetry
James, M.F. (a), Maheswaran, S. (b), Barjat, H. (a), Rueckert, D. (b),
Bate, S.T. (e), Howlett, D.R. (a), Tilling, L. (a), Smart, S.C. (a),
Pohlmann, A. (a), Hill, D.L.G. (c), Hajnal, J.V. (d), Upton, N. (a)
a) Neurology & GI CEDD, GlaxoSmithKline, Harlow, UK., b) Dept. of
Computing, Imperial College, London, UK., c) IXICO Ltd, London, UK.,
d) Imaging Sciences Dept., Imperial College, London, UK., e)
Statistical Sciences, GlaxoSmithKline, Harlow, UK.
In Alzheimer`s disease (AD) progressive brain volume changes are
observed, which correlate with clinical status and amyloid (Aβ42)
deposition. TASTPM transgenic mice over-express the AD associated
human proteins APP(K670N,M671L) x PS1(M146V) resulting in
progressive deposition of cerebral Aβ42.
To investigate the deposition of Aβ and its effects on brain structure,
as well as inflammatory processes, immunohistochemistry and
regional MRI volumetry were utilized. An advanced non-linear image
registration technique in combination with the LONI mouse atlas
(UCLA) was used to calculate the volumes of the 14 largest atlas
regions. We studied 17 TASTPM and 14 wildtype (WT) mice in vivo
from the age of 6 months (repeatedly imaging at 6,9,11,14 m).
Abundant APP was found already in young TASTPM (WT none)
resulting in a dramatic and widespread increase in Aβ42. The
inflammatory response was observed as considerable astrogliosis and
microgliosis. Between 6-11 months whole brain volumes of WT
increased significantly, but levelled thereafter. This sustained growth
has been reported in the literature. In TASTPM however, brain volume
growth is similar up to 11 month but continues afterwards. The
majority of individual brain regions also grew significantly in both
strains, but different temporal trends were found in several regions
with some growing in TASTPM while changing little in WT, including
cerebral cortex, hippocampal formation, and thalamus. A rationale for
these observations is based on the sheer volume of Aβ deposited and
resulting astrogliosis.
Volumetric MRI detects structural brain changes, which are consistent
with immunohistochemical findings and assumed to result from
amyloid deposition.
69.04
MRI measurements of diffusion, perfusion and T2 with proteomic
analysis in the rat hippocampus following status epilepticus
Choy M (1), Scott R C (1), Thomas D L (2), Gadian D G (1), Greene N
D E (1), Wait R (3), Leung K-Y (4), Lythgoe M F (1)
(1) UCL Institute of Child Health, London; (2) Department of Medical
Physics and Bioengineering, University College London, London; (3)
Kennedy Institute of Rheumatology Division, Imperial College London,
London; (4) William Harvey Research Institute, Bart`s and the London,
London.
Introduction Status epilepticus (SE) in humans may be associated
with hippocampal injury, epileptogenesis and development of temporal
lobe epilepsy. Diffusion (ADC), perfusion (CBF) and T2 MRI changes
have been reported in both clinical and experimental settings following
SE. However, the temporal relationships between these changes
remain uncertain. The aim of this study was to characterise diffusion,
perfusion and T2 in the lithium-pilocarpine model of SE in the rat and
proteomic analysis was used to investigate the underlying tissue
status.
MethodsSprague-Dawley rats were injected with lithium chloride
(3mEq/kg i.p.) 18 to 20h prior to either pilocarpine (30mg/kg) (n=6) or
saline (n=6). Diazepam (10mg/kg i.p.) was administered 90 min after
the onset of SE. MRI was performed pre-injections and on days 0, 1,
2, 3, 7, 14 and 21 days after SE. For the proteomics study (n = 6),
animals were imaged and sacrificed on day 2 for proteome analysis
using 2D gels and mass spectrometry.
Results and Discussion We have demonstrated that time-dependent
hippocampal changes in ADC, CBF and T2 occur following SE. These
changes peaked on day 2 and returned to baseline by day 7. The
time-dependence of these changes may indicate an opportunity for
early intervention and therefore we conducted proteomic analysis on
the hippocampus on day 2. We identified changes in proteins related
to stress (HSP-27), the cytoskeleton (alpha-tubulin, ezrin), and
neurogenesis (CRMP-2). Further studies are necessary to elucidate
the mechanisms that underlie these changes and the role that they
may play in epileptogenesis.
69.03
Pathologies in the thalamus of TASTPM transgenic mice model of
Alzheimer’s disease - characterisation by MRI, micro-CT and histology
Evans S C, Barjat H, Pohlmann A, Tilling L, Vidgeon-Hart M, Hayes, B.P.,
Upton, N., James, M.F.
Neurology and GI CEDD, GlaxoSmithKline, Harlow, UK
TASTPM transgenic (Tg) mice over-express the Alzheimer’s disease (AD)-
associated human proteins APP(K670N, M671L) x PS1(M146V). Cerebral
Aβ is progressively deposited, and is widespread at 6 month. The Tg model
will be most useful if plaque deposition is accompanied by
neurodegeneration, as in AD patients.
We repeatedly carried out in-vivo MR imaging of TASTPM and wildtype
(WT) strains from 6 to 14 months of age to try and measure temporal
neurodegenerative changes non-invasively in vivo. Some animals were
imaged post-mortem using MRI and micro-CT, the brains were then
analysed using histology. All MR images obtained were T2*-weighted. All
observations reported below are seen in Tg, but not in WT animals.
Serial in vivo MR images reveal the presence of progressive pathologies in
the thalamus of animals from 6 months of age. Post-mortem CT images
show areas of X-ray dense material in the thalamus; the latter coincide with
the areas seen by post-mortem MRI.
Histology shows elevated levels of astrocytes and glial cells (GFAP and
iba-1 respectively) and presence of amyloid deposits (1E8) in all areas of
the brain. In the thalamus, it shows co-accumulation of calcium (von Kossa)
and ferrous iron (positive Schmeltzer and negative Perl) with some amyloid
plaques. The distribution of calcium plaques coincides with that of the
features observed in CT and MR images.
The thalamic pathologies described may be the equivalent of calcifications
or micro-bleeds seen in the brains of AD patients.
69.05
Pharmacological challenge magnetic resonance imaging in rat brain
following cannabinoid receptor agonist THC, or the antagonist,
rimonabant
Stark J A, Dodd G, Williams S R, Luckman S M
1,2,4: Faculty of Life Sciences, 3: Imaging Science and Biomedical
Engineering, University of Manchester, Manchester M13 9PT.
Delta9-tetrahydrocannabinol (THC) increases feeding in satiated rats by
acting on central reward systems. It was suggested that cannabinoid
receptor 1 (CB1) antagonists/inverse agonists could treat obesity, and this
has led to the CB1 inverse agonist rimonabant to be tested in phase 3
clinical trials, despite a lack of information on its site of action. We have
used pharmacological challenge MRI to compare brain blood oxygen level
dependent (BOLD) maps produced by 1mg/kg THC with an anorectic dose
of rimonabant (1mg/kg).
THC and rimonabant had strikingly opposite effects. Rimonabant increased
BOLD signal in sensory and motor, as well as in limbic regions of the brain.
THC produced either decreased or no signal in these same areas. THC
increased BOLD signal in olfactory cortical areas and the anterior
amygdala, but had no effect in the hypothalamus – areas that displayed
decreased signal with rimonabant.
It is difficult to attribute regional brain activity to specific effects of the drug,
but these results suggest that rimonabant may reduce food intake by acting
on the limbic forebrain. This is supported by the fact that THC had weak
though consistently opposite effects in these areas. In addition, changes in
BOLD signal were observed in motor systems. This is consistent with
known actions of cannabinoids, though no altered motor behaviour
following this dose of rimonabant is reported in the literature.
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