Cortical GABAA CBZR and rCBF in Alzheimers disease: SPET studies with Partial Volume Effect Correcti

1
Cortical GABA-A CBZR and rCBF in Alzheimers
disease SPET studieswith Partial Volume Effect
Correction

• Mario Quarantelli
• Biostructure and Bioimaging Institute CNR
• Naples - Italy
• HBM2004 - PVEOut Satellite Meeting
• Budapest, 12 June 2004

2
CBF

• The progression from Mild Cognitive Impairment
  (MCI) to Alzheimers Disease (AD) is
  characterized by the increase in severity and
  extension of cerebral hypometabolism and regional
  cerebral blood flow (rCBF) Nestor 2003, already
  detectable in posterior cingulate, hippocampus
  and temporal neocortex in MCI patients.Concurrent
  ly, gray matter (GM) loss, essentially limited to
  hippocampal cortex in MCI Chetelat 2002,
  progresses into a more widespread cortical loss.

• Chetelat G, et al. Neuroreport 2002 131939-1943
• Nestor PJ, et al. Ann Neurol 200354343351

3
CBF

• It is not currently known weather this pattern of
  progression is characterized by a strict coupling
  of these two phenomena (i.e. GM loss explains the
  metabolism reduction as detected by FDG-PET and
  rCBF-SPET studies), or if metabolic impairment
  exceeds the rate of GM loss.Aim of our study was
  to compare rCBF decrease independently of GM loss
  in two groups of MCI and AD patients, using a
  ROI-based method for partial volume effect (PVE)
  correction which takes into account both WM and
  CSF.

4
CBF - METHODS

• 12 MCI subjects (mean age 74.8 yrs, MMSE 27.8
  range 24.9-30)
• 10 AD patients (mean age 79.5 yrs, MMSE 21.2,
  range 16.9-24)
• SPECT
• 64-slice brain-dedicated SPECT
• 20-30 min after 740-1110 MBq of 99mTc-HMPAO
• 120 steps, 3 angular step, 15 sec per step, 128
  x 128 matrix, pixel size 1.673mm, Butterworth
  filter (cut-off 0.9 cm-1, order10),
  attenuation correction (0.120 cm-1) using Changs
  algorithm Chang, 1987.
• Final FWHM 10.4mm (6mm axial)
• MRI
• Magnetization-prepared 3D T1-weighted fast-GrE
  images, TR/TE/TI 11/2/600ms, 1.5T, voxel size
  0.98x0.98x1.2mm
• Probabilistic MRI segmentation Ashburner J,
  2000 and co-registration to SPECT studies
  Friston KJ, 1995.

• Ashburner J, Friston KJ, NeuroImage 2000
  11805-21
• Chang, L. IEEE Trans Nucl Sci 198725 638-643
• Friston KJ, et al. Hum Brain Map 1995 2165189

5
CBF - METHODS

• VOI including cerebral lobes and hippocampus for
  each side, and a single region for cerebellum and
  posterior cingulate, were defined in the MNI
  space and adapted to each co-registered segmented
  GM using normalization parameters derived from
  the SPM99 affine normalization matrix Berkouk
  2003.
• For each VOI, uncorrected and PVE-corrected mean
  tracer concentrations were calculated Rousset
  OJ, 1998 Quarantelli M, 2003 and normalized by
  corresponding cerebellum values.
• Comparison between MCI and AD groups was carried
  out for each region by Student's T-test.
  Significance level was set to Plt0.05.

• Berkouk K, et al. 2003 HBM meeting Abs. 1017
• Quarantelli M, et al. J Nucl Med. 200445192-201
• Rousset OG, et al. J Nucl Med 199839904-911

6
77yo MCI
7
77yo AD
8
CBF - Methods
9
CBL-normalized rCBF(AD-MCI) / MCI
Mean percentage reduction in AD compared to MCI
patients. Data are reported before (uncorrected)
abd after (corrected) correctionfor partial
volume effects. Significant differences (Plt0.05)
are in yellow.
10
CBF CONCLUSIONS

• Metabolic/CBF changes in AD are paralleled by GM
  loss Baron JC, 2001a Karas GB, 2003. Accurate
  voxel-based comparisons of these changes have
  shown that the atrophy explains the GM
  hypometabolism with the exception of the
  posterior cingulate Baron JC, 2001b, an area
  known to be affected precociously in AD
  Minoshima S, 2000.
• Our results integrate these findings, showing in
  PVE-corrected rCBF-SPET data from AD patients, as
  compared to MCI, a similar pattern of posterior
  cingulate involvement independent of GM
  loss.Reduced metabolism in these regions may be
  related to remote functional disruption and/or by
  larger neuronal loss than expected from
  structural changes.
• While larger cohorts are needed to confirm these
  preliminary findings, longitudinal studies are
  needed to confirm this pattern of progression of
  the disease.

• Baron et al, NeuroImage 2001b 13S771
• Baron JC, et al. Neuroimage 2001a 14298-309
• Karas GB, et al. Neuroimage 2003 18895-907
• Minoshima S, et al. Ann Neurol 1997, 42 85-94

11
Cortical GABA-A CBZR loss measured with
123I-Iomazenil in Alzheimers disease a SPECT
study with Partial Volume Effect correction
Cortical synaptic/neuronal loss has been reported
in neuropathological studies of patients with AD
and may contribute to GM density changes
described recently in AD using VBM analysis of
structural MRI. PET/SPECT markers of GABA-A
central benzodiazepine receptors (cBZR) have been
proposed to detect in vivo early cortical
synaptic/neuronal loss in AD. Only few studies
have been reported with discordant results Meyer
M et al, Arch neurol 1995 52314 - Soricelli A,
et al. Eur J Nucl Med 1996231323
12
GABA-A CBZR
Aim of the study was to investigate whether
cortical synaptic/neuronal loss may be detected
in vivo in AD using SPECT with 123I-Iomazenil and
to assess how the measurement of these receptor
changes is affected by partial volume effect
(PVE). For this we used a voxel-based method for
PVE-correction which takes into account both WM
and CSF.

• Müller-Gartner HW, et al. J CBF Metab
  199212571-583
• Quarantelli M, et al. J Nucl Med. 200445192-201

13
GABA-A CBZR
14
GABA-A CBZR

• 5 AD patients (NINDS-ADRDA criteria mean age 70
  11 yrs, MMSE 194)
• 8 patients with MCI (746.5 yrs, MMSE 272)
• 3 healthy volunteers (605 yrs, MMSE 30)
• 20 minute SPECT acquisition, 180 min after
  injection
• brain-dedicated camera (Ceraspect 64 transaxial
  slices voxel size 1.673 mm
• Attenuation correction (Changs algorithm,
  attenuation factor 0.120 cm-1)
• These 'late images' were assumed to reflect
  essentially receptor binding.
• MRI 1.5T, CSE sequences providing 32 T1w
  (600/15) and PD/T2w (2400/15-90) 4mm-thick axial
  images Multiparametric segmentation
• GM, WM and CSF maps were co-registered to SPECT
  studies.
• VOI including frontal, parietal, temporal, and
  occipital lobes, hippocampus and posterior
  cingulate cortex for each side, and a single
  region for cerebellum, was defined in the MNI
  space and adapted to each co-registered segmented
  GM using the SPM99 affine normalization matrix.
• Uncorrected and PVE-corrected mean tracer
  concentrations were normalized by corresponding
  cerebellum values.
• Two tailed Student's T-test on CBL-normalized
  values.
• Significance level was set to Plt0.05.

15
CBZR preliminary results

• Before PVE-correction
• AD vs NV
• reduction bilaterally in all cortical regions
  except the occipital and right frontal cortices
  and left hippocampus
• MCI vs NV
• reduction in the left posterior cingulate and a
  trend in the right posterior cingulate.
• AD vs MCI
• reduction of 123I-Iomazenil bilaterally in the
  parietal and temporal cortices and posterior
  cingulate and in the right hippocampus.

16
CBZR preliminary results

• After PVE-correction
• AD vs NV
• reduction in the posterior cingulate bilaterally
  and in the left hippocampus
• MCI vs NV
• No significant differences
• AD vs MCI
• reduction in the posterior cingulate bilaterally

17
123-Iomazenil before PVE correction in AD, MCI
and Controls (C). Significant reduction in AD vs
Controls plt0.05 plt0.01 Significant
reduction in AD vs MCI s plt0.05 plt0.01.
18
123-Iomazenil after PVE correction in AD, MCI and
Controls Significant reduction in AD vs Controls
plt0.05 plt0.01 Significant reduction in AD
vs MCI plt0.05 plt0.01
19
CBZR - Conclusions

• These preliminary results provide two interesting
  observations 1) In AD patients the GABA-A-cBZD
  receptors are significantly reduced as compared
  to Controls and MCI in associative cortical areas
  including the hippocampus. 2) This reduction
  survives the PVE-correction in some cortical
  areas particularly vulnerable in AD (posterior
  cingulate cortex and, to a lesser extent, the
  hippocampus).
• Overall these findings suggest that GABA-A-cBZR
  alterations in AD parallel but also exceed
  structural changes as measured by MRI
  segmentation. Further data are required to
  confirm these findings in larger groups of
  subjects