Posterior cingulate hypometabolism in early Alzheimer's disease: what is the contribution of local atrophy versus disconnection?

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BRAIN
A JOURNAL OF NEUROLOGY
LETTERTO THE EDITOR
Posterior cingulate hypometabolism in early Alzheimer’s disease: what is the
contribution of local atrophy versus disconnection?
Gae ¨l Che ´telat,1Nicolas Villain,1Be ´atrice Desgranges,1Francis Eustache1and
Jean-Claude Baron2
1 Inserm-EPHE-Universite ´ de Caen/Basse-Normandie, Unite ´ U923, GIP Cyceron, CHU Co ˆte de Nacre, Caen, France
2 Department of Clinical Neurosciences, Neurology Unit, University of Cambridge, Cambridge, UK
Correspondence to: Gae ¨l Che ´telat,
Inserm-EPHE-Universite ´ de Caen/Basse-Normandie,
Unite ´ U923, GIP Cyceron,
Bd H. Becquerel,
BP 5229, 14074 Caen Cedex,
France
E-mail: chetelat@cyceron.fr
Sir, Garden et al. (2009) reported an important experimental study
highlighting a potential mechanism for neuronal dysfunction
distant from the site of damage, specifically a loss of synaptic
plasticity in the retrosplenial/posterior cingulate cortex (PCC)
after anterior thalamic lesion in the rat. In the discussion section
of their article, they make the assumption that this phenomenon
plays a role in the early episodic memory impairment characteriz-
ing Alzheimer’s disease: the PCC would be disconnected from the
anterior thalamic nucleus—affected by early neuronal/synaptic
loss—through disruption of the cingulum bundle. This would in
turn lead to PCC hypometabolism, which occurs very early in
Alzheimer’s disease and already at the stage of amnestic mild
cognitive impairment (Minoshima et al., 1997; Che ´telat et al.,
2003a, b). The study by Garden et al. (2009) is therefore
important for the understanding of the pathophysiology of the
memory impairment that characterizes early Alzheimer’s disease,
astheproposedunderlyingsynaptic
amenable to specific pharmacological modulation.
Garden et al. (2009) also allude to the current debate about
the relative importance of disconnection versus local atrophy/
direct neuronal damage in the PCC hypometabolism observed in
amnestic mild cognitive impairment and early Alzheimer’s disease.
They write: ‘The notion that the retrosplenial/posterior cingulate
hypometabolism in Alzheimer’s disease is solely due to a discon-
nection from sites thought to atrophy prior to the retrosplenial
cortex, such as the hippocampus or anterior thalamus (Che ´telat
et al., 2008; Villain et al., 2008) is, however, probably incorrect.’
We thank them for citing our work, but feel they have somewhat
misquoted us when using the term ‘solely’. As a matter of fact,
mechanismcouldbe
we fully agree with their statement that disconnection is not the
only mechanism for PCC hypometabolism in Alzheimer’s disease
and have consistently stated so in our publications (Che ´telat et al.,
2008; Villain et al., 2008). First of all, early studies that assessed
the effect of correction of the 2-fluoro-2-deoxy-D-glucose-
positron emission tomography (18)fluoro-deoxyglucose positron
emission tomography (FDG-PET) data for partial volume effects
demonstrated that atrophy significantly contributes to the PCC
hypometabolism observed in raw FDG-PET images in Alzheimer’s
disease. For instance, Ibanez et al. (1998) found that following
partial volume effect correction, PCC hypometabolism, though still
present, had notably reduced. Using voxel-based morphometry,
we were among the first to provide in vivo evidence of significant
grey matter volume loss in the PCC in both Alzheimer’s disease
(Baron et al., 2001) and amnestic mild cognitive impairment
(Che ´telat et al., 2002), providing a straightforward explanation
for the above findings. Thus, there can be no doubt that PCC
hypometabolism in raw FDG-PET images partly reflects grey
matter volume loss. However, we also showed, by directly
comparing the degree of grey matter atrophy and partial
volume effect-corrected hypometabolism in early Alzheimer’s
disease, that a significant fraction of PCC hypometabolism is
due to mechanisms other than local atrophy, and speculated
that this could represent, at least in part, disconnection effects
from the hippocampal region via the cingulum bundle (Che ´telat
et al., 2008). In a subsequent study, we then provided strong
support to this hypothesis by combining voxel-based morpho-
metry and FDG-PET, demonstrating a significant correlation
between cingulum bundle disruption and PCC hypometabolism
doi:10.1093/brain/awp253Brain 2009: 132; 1–2 |
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(Villain et al., 2008). Thus, disconnection also plays a part in the
observed PCC hypometabolism.
Additional intriguing issues, somewhat tricky to address, are
(i) does PCC hypometabolism remain related to local atrophy
even after correcting for partial volume effects, as a reflection of
local burden of neuronal damage? and (ii) do additional mechan-
isms also contribute to PCC hypometabolism above and beyond
actual volume loss and disconnection effects? To address these,
we have reanalysed our data from Villain et al. (2008) aiming to
assess the independent contribution of local atrophy and discon-
nection to the residual PCC hypometabolism after correction
for partial volume effects, and the remaining part of PCC
hypometabolism not explained by these two factors. Using the
mean individual metabolic and grey matter Z-scores in the clusters
of interest, we found partial volume effect-corrected PCC
hypometabolism to be significantly related to local atrophy
(Pearson r2=0.42; P=0.003) as well as cingulum bundle volume
(Pearson r2=0.7; P=10?5; Fig. 1, blue slopes). We then included
both the cingulum bundle white matter Z-scores and the PCC grey
matter Z-scores as independent variables in a multiple regression
analysis with PCC hypometabolism as the dependent variable.
The model was found to be highly significant as a whole (multiple
r2=0.70; P=10?5); the cingulum bundle volume alone was found
to provide a significantly independent contribution to this model
(semi-partial r2=0.28; P=10?3), but PCC atrophy alone did not
independently contribute to the model (semi-partial r250.01;
p=0.68; Fig. 1, orange slopes). Thus, overall these data suggest
that local atrophy does not independently contribute to PCC
hypometabolism after partial volume effect correction, i.e. FDG
uptake per gram of brain tissue is not influenced by factors
conducting to, associated with or downstream of, local atrophy,
while disconnection explains a large fraction (here 70%) of this
measurement. Beyond methodological factors, the remaining
unexplained 30% of total variance probably reflects other non-
atrophy-related functional alterations, e.g. amyloid deposition
and/or disconnection from other bundles. We are currently
analysing data from a longitudinal study which will hopefully
help in elucidating the temporal sequence of events and the
causal relationships between these.
References
Baron JC, Che ´telat G, Desgranges B, Perchey G, Landeau B, de la
Sayette V, et al. In vivo mapping of gray matter loss with voxel-
based morphometry in mild Alzheimer’s Disease. NeuroImage 2001;
14: 298–308.
Che ´telat G, Desgranges B, de la Sayette V, Viader F, Eustache F,
Baron JC. Mapping gray matter loss with voxel-based morphometry
in mild cognitive impairment. NeuroReport 2002; 13: 1939–43.
Che ´telat G, Desgranges B, de la Sayette V, Viader F, Berkouk K,
Landeau B, et al. Dissociating atrophy and hypometabolism impact
on memory in mild cognitive impairment. Brain 2003a; 126: 1955–67.
Che ´telat G, Desgranges B, de la Sayette V, Viader F, Eustache F,
Baron JC. Mild cognitive impairment: FDG-PET predicts who is to
rapidly convert to Alzheimer’s disease. Neurology 2003b; 60: 1374–7.
Che ´telat G, Desgranges B, Landeau B, Me ´zenge F, Poline JB, de la
Sayette V, et al. Direct voxel-based comparison between grey
matter hypometabolism and atrophy in Alzheimer’s disease. Brain
2008; 131: 60–71.
Garden DL, Massey PV, Caruana DA, Johnson B, Warburton EC,
Aggleton JP, et al. Anterior thalamic lesions stop synaptic plasticity
in retrosplenial cortex slices: expanding the pathology of diencephalic
amnesia. Brain 2009; 132: 1847–57.
Iba ´n ˜ez V, Pietrini P, Alexander GE, Furey ML, Teichberg D, Rajapakse JC,
et al. Regional glucose metabolic abnormalities are not the result of
atrophy in Alzheimer’s disease. Neurology 1998; 50: 1585–93.
Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE.
Metabolic reduction in the posterior cingulate cortex in very early
Alzheimer’s disease. Ann Neurol 1997; 42: 85–94.
Villain N, Desgranges B, Viader F, de la Sayette V, Me ´zenge F,
Landeau B, et al. Relationships between hippocampal atrophy, white
matter disruption and gray matter hypometabolism in Alzheimer’s
disease. J Neurosci 2008; 28: 6174–81.
Figure 1 Contribution of local atrophy and cingulum bundle disruption to partial volume effect-corrected PCC hypometabolism. PCC
hypometabolism is significantly correlated to both cingulum white matter atrophy (A) and PCC grey matter atrophy (B) when assessed
separately (blue slopes). However, only cingulum bundle disruption remained significantly related to partial volume effect-corrected
PCC hypometabolism when controlling for PCC atrophy (A, orange slopes), whereas PCC atrophy did not independently contribute
to PCC hypometabolism when cingulum white matter atrophy was controlled (B, orange); PVE=partial volume effect.
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