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Similar amyloid-β burden in posterior cortical atrophy and Alzheimer's disease

Leonardo Cruz de Souza, Fabian Corlier, Marie-Odile Habert, Olga Uspenskaya, Renaud Maroy, Foudil Lamari, Marie Chupin, Stéphane Lehéricy, Olivier Colliot, Valérie Hahn-Barma, Dalila Samri, Bruno Dubois, Michel Bottlaender, Marie Sarazin
DOI: http://dx.doi.org/10.1093/brain/awr130 2036-2043 First published online: 24 June 2011


While the clinical presentation of posterior cortical atrophy is clearly distinct from typical Alzheimer's disease, neuropathological studies have suggested that most patients with posterior cortical atrophy have Alzheimer's disease with an atypical visual presentation. We analysed in vivo pathophysiological markers of Alzheimer's disease such as cerebrospinal fluid biomarkers and positron emission tomography imaging with 11C-labelled Pittsburgh compound-B in posterior cortical atrophy to determine whether biochemical profile and fibrillar amyloid-β burden topography are associated with the clinical presentation. Nine patients with posterior cortical atrophy and nine with typical Alzheimer's disease individually matched for age, duration and severity of the disease and 10 cognitively normal age-matched controls were included. 11C-labelled Pittsburgh compound-B images were analysed both using volumes of interest and on a voxel-wise basis using statistical parametric mapping, taking into account the individual regional cortical atrophy. Cerebrospinal fluid biomarkers did not differ between posterior cortical atrophy and patients with Alzheimer's disease. Compared with normal controls, both posterior cortical atrophy and Alzheimer's disease groups showed increased 11C-labelled Pittsburgh compound-B uptake. No significant difference was found in regional or global 11C-labelled Pittsburgh compound-B binding between posterior cortical atrophy and Alzheimer's disease groups with both volumes of interest and voxel-wise basis using statistical parametric mapping methods. Our findings demonstrate that cerebrospinal fluid biomarkers and positron emission tomography imaging with 11C-labelled Pittsburgh compound-B may be useful in identifying an atypical visual form of Alzheimer's disease. The similar topography of fibrillar amyloid-β deposition between typical Alzheimer's disease and posterior cortical atrophy groups suggests that, although amyloid-β accumulation plays a critical role in the pathogenesis of Alzheimer's disease, other factors such as neurofibrillary tangles may contribute to the different clinical features observed in posterior cortical atrophy.

  • Alzheimer's disease
  • posterior cortical atrophy
  • Pittsburgh compound-B


Posterior cortical atrophy (PCA) can be defined as an atypical form of Alzheimer's disease, as shown by neuropathological studies (Renner et al., 2004; Tang-Wai et al., 2004; Alladi et al., 2007). However, the clinical presentation of PCA is clearly distinct from typical Alzheimer's disease (Dubois et al., 2010). In PCA, disease onset is characterized by visual disturbances, followed by an impairment of visuospatial skills, while episodic memory is relatively spared (McMonagle et al., 2006). Neuroimaging shows atrophy and hypoperfusion/hypometabolism that predominates in the parieto-occipital cortex regions (Lehmann et al., 2009), with a relative sparing of the temporal regions (Aharon-Peretz et al., 1999; Nestor et al., 2003). This clinical presentation contrasts with typical Alzheimer's disease, which is characterized by an early episodic memory deficit associated with prominent medial temporal lobe atrophy.

Pathophysiological markers can help identify the underlying aetiology of PCA (Dubois et al., 2010). CSF biomarker levels are considered to reflect Alzheimer pathology and can be useful in isolating patients with an atypical Alzheimer's disease phenotype (Baumann et al., 2010; de Souza et al., 2011). 11 C-labelled Pittsburgh compound-B (11 C-PIB)-PET scanning measures the fibrillar amyloid-β deposition (Ikonomovic et al., 2008). Only two cases of PCA have been published with details of 11 C-PIB binding showing a high amyloid-β burden in the occipital cortex (Ng et al., 2007; Migliaccio et al., 2009), which is not the most affected region in Alzheimer's disease (Kemppainen et al., 2006). Better characterization of CSF and PET amyloid deposition profiles in patients with PCA would improve diagnosis and facilitate inclusion in clinical trials of Alzheimer's disease-modifying drugs.

We aimed to analyse both CSF biomarkers and 11 C-PIB-PET profiles in subjects with PCA. Because PCA and Alzheimer's disease are likely to have the same underlying neuropathological process, we hypothesize that the two groups would present similar CSF and PIB binding patterns. Therefore, we studied the topography of amyloid deposition in PCA compared with Alzheimer's disease to examine whether the different clinical presentations of PCA and typical Alzheimer's disease were associated with a distinct distribution and burden of fibrillar amyloid-β deposition.

Materials and methods


Nine patients with PCA were enrolled on the basis of following diagnostic criteria (McMonagle et al., 2006; Alladi et al., 2007): (i) insidious onset and gradual progression of cognitive impairment beginning with visual complaints; (ii) presentation with visuospatial deficits with intact primary visual function; (iii) features suggestive of Bálint's syndrome (optic ataxia, ocular apraxia and simultagnosia) associated or not with Gerstmann's (acalculia, agraphia, left–right disorientation and finger agnosia) syndrome; (iv) proportionally less episodic memory impairment; (v) relatively preserved insight; and (vi) glucose hypometabolism on 18 F-fluorodeoxyglucose-PET examination and prominent cortical atrophy in the posterior cortical region on MRI. A complete Bálint's syndrome was observed in seven of nine patients with PCA, while incomplete Bálint's syndrome was present in two of nine subjects (isolated simultagnosia for one patient, and simultagnosia with oculomotor apraxia for the other). In addition, complete Gerstmann's syndrome was observed in three of nine patients with PCA; incomplete Gerstmann's syndrome was present in six of nine patients. Ideomotor apraxia, acalculia, agraphia and environmental disorientation were observed for eight of nine patients, visual agnosia, hemineglect and finger agnosia were present in seven of nine patients and dressing apraxia in five of nine patients with PCA (refer to Supplementary Table 1 for details).

Nine typical patients with Alzheimer's disease were individually matched with subjects with PCA for age, duration of disease and disease severity assessed by the Clinical Dementia Rating scale score. Individual matching was used to avoid a selection bias caused by these parameters. All subjects with Alzheimer's disease were selected according to the New Research Criteria (Dubois et al., 2007, 2010), which include (i) progressive episodic memory impairment, characterized by a low free recall not normalized with cueing; (ii) CSF Alzheimer's disease profile, defined as score below 0.8 for the ratio of amyloid-β42:tau, calculated with the formula amyloid-β42/[240 + (1.18 × T-tau)] (Visser et al., 2009); and (iii) clinical dementia rating scale ≥0.5.

Ten healthy elderly controls were recruited for the study according to the following criteria: (i) Mini-Mental State Examination score ≥28/30 and clinical dementia rating scale = 0; (ii) no history of neurological or psychiatric disorders; and (iii) no memory complaint or cognitive deficit.

Subjects were not included in the study if they presented any of the following criteria: (i) systemic illnesses that could interfere with cognitive functioning; (ii) extrapyramidal signs or neurological history suggestive of Parkinson's disease with dementia, progressive supranuclear palsy, corticobasal degeneration or dementia with Lewy bodies; (iii) vascular lesions on MRI or neurological history suggestive of vascular dementia; or (iv) depression assessed with a score >20 on the Montgomery-Asberg Depression Rating Scale (MADRS; Montgomery and Asberg, 1979).

Blood samples were drawn to characterize APOE genotypes. The controls underwent the same procedures as did the patients with PCA and Alzheimer's disease, except for lumbar puncture, which was not proposed due to ethical reasons.

The study was conducted by the French National Institute of Health and Medical Research (INSERM; ANR-07-LVIE-002-01) and was approved by the Ethics Committee of Pitié-Salpêtrière Hospital. All subjects provided written informed consent before participating.

Clinical, functional and cognitive assessment

All subjects (healthy controls, Alzheimer's disease and PCA) underwent a clinical and neuropsychological examination that included the Mini-Mental State Examination (Folstein et al., 1975), the clinical dementia rating scale (Morris, 1993) and tests for assessing verbal episodic memory, executive functions, working memory, gesture praxis and visuoconstructive function. In addition, subjects with PCA underwent a specific ‘posterior neuropsychological battery’ assessing hemineglect, spatial disorientation, body schema distortion, Bálint's and Gerstmann's syndromes (Kas et al., 2011).

Cerebrospinal fluid biomarker analysis

CSF samples obtained by lumbar puncture were processed with the same procedures described previously (de Souza et al., 2011) to obtain CSF levels of total tau (T-tau), phosphorylated tau at threonine 181 (P-Tau) and amyloid-β peptide 1-42 (amyloid-β42) by using enzyme-linked immunosorbent assay kits (Innogenetics), according to the manufacturer's instructions. All operators were blind to clinical information.

Magentic resonance imaging procedure

In each participant, the imaging data were collected using a 3 T Siemens 32-channel TRIO TIM system using 12-channel head coil for signal reception. The MRI examination included a 3D T1-weighted volumetric magnetization-prepared rapid-gradient echo sequence with repetition time = 2300 ms, echo time = 3.43 ms, inversion time = 900, 256 × 256 matrix, axial field of view and slice thickness 1 mm. This sequence provided a high grey/white matter contrast-to-noise ratio and allowed for excellent segmentation and accurate coregistration with the PET images.

Positron emission tomography imaging procedure

Data acquisition

PET examinations were performed with a High Resolution Research Tomograph (HRRT, Siemens Medical Solution), the camera with the highest available spatial resolution for brain imaging. The spatial resolution for the HRRT scanner was 2.5 mm with an absolute sensitivity of 6% for a point source in the centre of the field of view. The HRRT had an axial field of view of 25 cm and a transaxial field of view of 31.2 cm. It allowed the reconstruction of 207 slices of 1.1 mm thickness. Subjects were positioned in the tomograph with the head maintained using an individually moulded head holder. A 6-min brain transmission scan was performed before injection of each radioligand using a 137Cs point source to correct the emission scan for tissue attenuations. 11C-PIB (mean 364 ± 47 MBq) was injected intravenously, and PET acquisitions lasted 90 min. Twenty-five images were reconstructed with a scan duration starting from 1 min and increasing up to 10 min during the experiment. All images were reconstructed with an accelerated list-mode, ordinary Poisson ordered-subset expectation maximization (OP-OSEM) algorithm, including an experimental stationary model of the scanner spatial resolution that allowed for a lowering or the statistical noise at the voxel level in the reconstructed images without degrading spatial resolution (Sureau et al., 2008). This method improved quantitative accuracy by reducing the partial volume effects.

Volume of interest analysis

Parametric images were created using Brainvisa software (http://brainvisa.info). The cerebellum was used as a reference region in the analysis because this region has been found to be spared from amyloid plaque accumulation (Joachim et al., 1989). Standard uptake value parametric images were constructed on late images over 50–70 min because this time schedule has been shown to be more accurate (Lopresti et al., 2005). Standard uptake value-ratio parametric images were constructed by dividing each pixel by the corresponding value obtained in the cerebellum. The parametric images were coregistered individually with the corresponding 3D magnetic resonance T1 images using the Brainvisa software.

All volumes of interests were delineated on the individual MRI scans for each subject as described below.

Segmentation: the T1 weighted images were segmented with the Brainvisa software. The cortical and sub-cortical grey matter, white matter and cerebellum were delineated using histogram analysis, threshold methods and morphological operators. A parcellation of the cortex into 76 structures was then performed in three steps: (i) non-linear registration of the subject's segmented cortex on the Montreal Neurological Institute grey matter template and application of the inverse transformation to the Automated Anatomic Labeling atlas; (ii) masking of this resampled volume of labels by the segmented cortex structure and filling of the cortex mask using a Voronoi diagram; and (iii) minimization of the gyri interface distance to the nearest sulci bottoms extracted using a regional deformable model. The amygdala and hippocampi were automatically segmented in each individual using the T1-weighted MRIs and the SACHA software (Chupin et al., 2009).

Automated Anatomic Labeling segmentation provided values of 11C-PIB fixation in 76 anatomical regions. The volumes of interest were defined separately for the left and right hemispheres and were pooled into greater anatomical regions based on anatomical relationships to obtain a mean 11C-PIB-standard uptake value-ratio for each region, as described in the legend of Fig. 1. As a measure of global amyloid burden, we calculated a 11C-PIB global index, representing the subject's mean standard uptake value-ratio in all the defined regions (Fig. 1).

Figure 1

Scatter plots showing 11C-PIB-standard uptake value-ratio in anatomical regions across groups [healthy controls (diamonds), Alzheimer's disease (circles), PCA (triangles)]. Anatomical regions were pooled from volumes of interests provided by Automated Anatomic Labeling segmentation and were defined as the following: (i) frontal cortex by grouping orbitofrontal, polar prefrontal and dorsolateral cortex; (ii) anterior cingulate; (iii) medium cingulated; (iv) posterior cingulate; (v) precuneus; (vi) occipital cortex by grouping calcarine cortex, occipital cortex and cuneus; (vii) temporal cortex by grouping anterior and lateral temporal cortex; (viii) hippocampus; and (ix) parietal cortex by grouping inferior and superior parietal cortex and the parietotemporal junction. The 11C-PIB global index representing the subject's mean standard uptake value-ratio in the regions is described above. AD = Alzheimer's disease.

Voxel-based analysis and preprocessing

MRI data were spatially normalized using SPM5 (Wellcome Trust Centre for Neuroimaging) and the Montreal Neurological Institute template, and then segmented to isolate the grey matter partition. In an effort to avoid a bias group effect resulting from spatial normalization, the procedure included the creation of a customized template of the grey matter using the MRI data from the whole combined patient and control samples (n = 28). Grey matter data were then renormalized using this customized template. A whole grey matter mask was obtained by thresholding the grey matter density average image above a value of 0.2, corresponding to a 20% chance that the voxel belongs to the grey matter (Chetelat et al., 2008).

Four 11C-PIB PET frames of 5 min each from 50 to 70 min post-injection were realigned with SPM5, and a mean volume was calculated from these four frames for each subject. The mean 11C-PIB-PET volumes were then coregistered to their corresponding MRI and spatially normalized, applying the transformation parameters obtained from MRI normalization. A partial volume effect was minimized by (i) the reconstruction algorithm described above (Sureau et al., 2008); and (ii) by multiplying each normalized mean 11C-PIB image by its corresponding whole grey matter mask. Each partial volume effect corrected 11C-PIB image was then divided by its corresponding mean cerebellum PIB standard uptake value, resulting in parametric standard uptake value-ratio images. The mean cerebellum activity was obtained from a custom mask drawn on the Montreal Neurological Institute single subject MRI provided by SPM. The PIB-standard uptake value-ratio images were then smoothed (full width at half maximum = 10 mm).

Statistical analysis

The clinical data, CSF biomarker levels, mean 11C-PIB-standard uptake value-ratio in each volume of interest and global PIB index group were compared between the PCA, Alzheimer's disease and healthy controls groups using a non-parametric Kruskal–Wallis one-way analysis of variance. The homogeneity of variances was assessed with the Levene and Brown-Forsythe tests. The Bonferroni correction for multiple comparisons was applied. The chi-square test was used to compare gender ratios. An alpha (significance) level of 0.05 was chosen. All statistical analyses were performed using PASW Statistics 18 (© SPSS Inc). For SPM analyses, the statistical threshold was set at P < 0.001, and false discovery rate corrected.


Subjects characteristics

Clinical characteristics of subjects with PCA, Alzheimer's disease and healthy controls are presented in Table 1. The Mini-Mental State Examination score did not differ between the PCA and Alzheimer's disease groups, whereas both groups significantly differed from the healthy control group (P < 0.001).

View this table:
Table 1

Demographic and clinical data of studied groups

PCAAlzheimer's diseaseControls
Number of subjects9910
Age (years)62.9 ± 3.5 (59.5–69)62.0 ± 2.7 (58–65.5)65.8 ± 6.8 (59–75.5)
Education (years)12.6 ± 2.6§ (9–15)14.7 ± 1.0 (12–15)13.3 ± 2.35 (9–15)
Disease duration (years)2.1 ± 1.8 (1–6)2.6 ± 1.3 (1–5)
Mini-Mental State Examination17.1 ± 5.9** (9–27)19.4 ± 3.8** (15–25)29.2 ± 1.0 (27–30)
Clinical dementia rating scale0.5, n = 30.5, n = 40 for all subjects
1, n = 31, n = 3
2, n = 32, n = 2
Amyloid-β42 (pg/ml)303 ± 73 (209–400)236 ± 92 (125–386)NA
T-tau (pg/ml)511 ± 290 (319–1183)540 ± 266 (175–1106)NA
P-tau (pg/ml)76 ± 34 (45–143)86 ± 28 (29–123)NA
Ratio of amyloid-β42:Tau0.4 ± 0.1 (0.2–0.6)0.3 ± 0.1 (0.1–0.4)NA
  • Data are presented as mean ± standard deviation (min–max).

  • §P < 0.05 versus Alzheimer's disease subjects; *P < 0.05 versus controls; **P < 0.001 versus controls. NA = not applicable.

Cerebrospinal fluid biomarker analysis

CSF biomarker levels in the PCA and Alzheimer's disease groups are presented in Table 1. No statistical differences were found between the PCA and Alzheimer's disease groups for amyloid-β42, T-tau, P-tau levels or for the amyloid-β42:Tau ratio. In accordance with the inclusion criteria, individual analysis showed that all patients with Alzheimer's disease had abnormal ratios of amyloid-β42:Tau. All patients with PCA had a CSF Alzheimer's disease profile, and the highest amyloid-β42:Tau ratio observed in this group was 0.6.

Pittsburgh compound-B: region of interest analysis

The Alzheimer's disease and PCA groups showed higher global 11C-PIB index and higher 11C-PIB uptake values in all regions of interest when compared with normal controls, except for the hippocampal region (Table 2). The mean PIB indices were identical in the PCA and Alzheimer's disease groups, and no significant differences in regional PIB uptake were detected between both groups in any region of interest.

View this table:
Table 2

Neocortical mean (±SD) 11C-PIB standard uptake value-ratio in anatomical regions

Healthy controls (n = 10)Alzheimer's disease (n = 9)PCA (n = 9)
Frontal1.30 (±0.17)2.66 (±0.97)*2.57 (±0.86)* NS
Anterior cingulate1.23 (±0.19)2.69 (±0.73)*2.85 (±0.55)* NS
Medium cingulate1.32 (±0.17)2.79 (±0.86)*2.89 (±0.61)* NS
Posterior cingulate1.29 (±0.29)2.53 (±0.84)*2.47 (±0.64)* NS
Precuneus1.24 (±0.18)2.79 (±0.88)*2.79 (±0.80)* NS
Occipital1.26 (±0.16)2.23 (±0.72)*2.12 (±0.54)* NS
Temporal1.11 (±0.13)1.88 (±0.63)*1.95 (±0.48)* NS
Hippocampus1.24 (±0.20)1.22 (±0.31)1.36 (±0.16) NS
Parietal1.26 (±0.15)2.66 (±0.83)*2.57 (±0.84)* NS
Global index1.22 (±0.15)2.37 (±0.71)*2.35 (±0.57)* NS
  • *Significant (P < 0.001) when compared with healthy group; NS = non-significant (P > 0.05) when compared with Alzheimer's disease group.

Individual analysis showed that one patient with Alzheimer's disease had no significant 11C-PIB uptake regardless of the region studied. This 65-year-old female had a typical clinical history of Alzheimer's disease, with onset of memory deficit 2 years before inclusion in the study. The Mini-Mental State Examination was 19/30, and the clinical dementia rating scale was 0.5. The CSF analysis revealed a biological profile of Alzheimer's disease with a low amyloid-β42 level (125 pg/ml) and an unusually high increase of T-tau (1016 pg/ml) and P-tau (123 pg/ml) levels. The EEG was normal. The clinical follow-up (18 months) was in agreement with the diagnosis. There was no argument for a frontotemporal dementia on clinical and neuroimaging investigations (MRI and fluorodeoxyglucose-PET). A 60-year-old female with PCA (Mini-Mental State Examination = 14; clinical dementia rating scale = 1) had a global 11C-PIB index overlapping with the highest score measured in controls, although regional analysis showed a high 11C-PIB uptake in the anterior and medium cingulate and occipital cortices. The CSF biomarkers showed a low amyloid-β42 level (246 pg/ml) with normal T-tau (336 pg/ml) and high P-tau levels (67 pg/ml) and an abnormal ratio of amyloid-β42:Tau (0.38).

Pittsburgh compound-B: voxel-wise comparisons

Compared with normal controls, patients with Alzheimer's disease showed significant symmetrical 11C-PIB binding throughout the frontal and parietal cortices, precuneus and cingulate regions (Fig. 2A), and patients with PCA showed diffuse and symmetric 11C-PIB binding in the frontal, parietal, temporal cortices, cingulate and precuneus (Fig. 2B). Direct SPM comparison of the two patient groups showed no voxel in which PIB uptake was greater in one or another group, even at a lower threshold of P < 0.001 uncorrected for multiple comparisons.

Figure 2

Topography of 11C-PIB standard uptake value-ratio in the grey matter of nine patients with Alzheimer's disease (A) and in the grey matter of nine patients with PCA (B) compared with 10 normal healthy controls. In both the Alzheimer's disease and PCA group, increased 11C-PIB standard uptake value-ratio involves widespread areas in the frontal, parietal, temporal and posterior cingulate cortices (significance threshold set at P < 0.001 corrected for false discovery rate).


In our study, we used CSF biomarkers and 11C-PIB-PET amyloid binding, which are markers of Alzheimer's disease lesions, to investigate in vivo the neuropathological process of patients with PCA. The positivity of both pathophysiological markers indicated the presence of Alzheimer pathology in favour of the diagnosis of atypical Alzheimer's disease. In addition, using two different methods of analysis, no difference in the load and topography of amyloid-β deposition assessed by 11C-PIB-PET was observed between the PCA and Alzheimer's disease groups, suggesting that amyloidosis cannot explain the differences in the Alzheimer's disease/PCA clinical presentations.

PCA is a rare disease, and we included a small number of patients in our analysis. To avoid selection bias, we individually matched each patient with PCA with a patient with Alzheimer's disease for age, duration of disease and disease severity. Patients with PCA had a similar profile of CSF biomarkers as compared with patients with Alzheimer's disease. Neuropathological studies demonstrated that the combination of amyloid-β42, T-tau and P-tau levels in ante-mortem CSF predicted the presence of Alzheimer's disease-associated pathological changes with high accuracy, supporting the idea that these CSF changes are a surrogate marker for the diagnosis of Alzheimer's disease (Bian et al., 2008; Tapiola et al., 2009). Previous studies have also suggested that CSF biomarkers may be useful to identify in vivo atypical focal forms of Alzheimer's disease such as PCA (Baumann et al., 2010; de Souza et al., 2011), although these observations were not supported by 11C-PIB-PET or autopsy data. The present study extends these results by providing molecular imaging support.

PIB binding is highly selective for insoluble fibrillar amyloid-β deposits. Direct correlation of in vivo 11C-PIB retention with quantitative analyses of amyloid-β plaques was demonstrated in a post-mortem study (Ikonomovic et al., 2008) and supports the validity of 11C-PIB-PET imaging as a method for the in vivo evaluation of amyloid-β plaque burden. High PIB uptake was observed in 80–100% of patients with Alzheimer's disease (Rowe et al., 2007; Rabinovici et al., 2010). In the current study, the CSF diagnosis of Alzheimer's disease in the PCA group was in accordance with the 11C-PIB-PET imaging showing higher 11C-PIB binding in subjects with PCA as compared with controls, and similar PIB binding as compared with patients with Alzheimer's disease. One subject with PCA had a PIB index that overlapped with the control values, although the subject had a biological CSF diagnosis of Alzheimer's disease. Interestingly, regional analysis showed high PIB binding in the anterior and median cingulate regions and a milder increase in the occipital cortex. One patient with Alzheimer's disease did not show evidence of elevated 11C-PIB binding, despite having the typical Alzheimer's disease clinical presentation and CSF biomarkers profile. Failure of 11C-PIB to detect amyloid-β pathology in Alzheimer's disease has already been reported (Rabinovici et al., 2010.), even in one patient with a pathological confirmation of Alzheimer's disease (Cairns et al., 2009).

Taken together, CSF biomarkers and 11C-PIB-PET provided arguments to establish in vivo the diagnosis of atypical Alzheimer's disease in patients with PCA. Clinicopathological investigations have demonstrated that Alzheimer's pathology is the most frequent cause of PCA, accounting for 80–100% of all cases (Renner et al., 2004; Tang-Wai et al., 2004; Alladi et al., 2007). Other diagnoses such as Lewy-body dementia, corticobasal degeneration and Creutzfeldt–Jakob (Renner et al., 2004) are rare. The fact that all patients with PCA in our study had no parkinsonism and had a disease onset characterized by visual disturbance could explain the homogeneity of our data. Future studies including autopsy diagnoses are needed to confirm our findings.

An unresolved challenge remains how to explain the differences in clinical presentation between PCA and Alzheimer's disease despite a similar burden of amyloidosis. PCA is characterized by early higher order visual deficits (Benson et al., 1988). Patients develop features of Bálint's syndrome (ocular apraxia, optic ataxia and simultanagnosia), Gerstmann's syndrome (acalculia, agraphia, finger agnosia, and left–right disorientation), visual agnosia and transcortical sensory aphasia, whereas episodic memory is preserved or only mildly impaired. Structural and functional neuroimaging has also demonstrated parieto-occipital atrophy and hypoperfusion/hypometabolism in a focal pattern that is clearly different from Alzheimer's disease (Nestor et al., 2003; Schmidtke et al., 2005; Lehmann et al., 2009; Kas et al., 2011).

One way to understand this singular clinical presentation of PCA is to assess the amyloid topography between both diseases in order to evaluate whether amyloidosis is related to the atypical visual form of Alzheimer's disease. Descriptive data about 11C-PIB binding in PCA are scarce. In two PCA cases, 11C-PIB uptake was increased in the occipital (Ng et al., 2007) and right calcarine cortices (Kambe et al., 2010). We did not confirm higher 11C-PIB uptake in the posterior cortical regions with our larger sample of nine patients with PCA who fulfilled strict inclusion criteria. No significant differences in 11C-PIB burden and distribution between patients with PCA and Alzheimer's disease were observed either using a region of interest method or a voxel-based approach. The absence of a relationship between the clinical symptoms of Alzheimer's disease and amyloid deposition is supported by several arguments: (i) PIB binding in Alzheimer's disease was not correlated with the severity of dementia assessed by the Mini-Mental State Examination (Engler et al., 2006) or the clinical dementia rating scale (Jack et al., 2009); (ii) amyloid deposition remains stable during Alzheimer's disease follow-up (2 years) despite further decreases in cognitive function and cortical glucose metabolism (Engler et al., 2006); (iii) the differences in clinical presentation between the early and late onset Alzheimer's disease groups was not related to amyloid burden (Rabinovici et al., 2010); and (iv) the progression of the amyloid deposition in the human brain (from neocortical regions to cerebellum) does not correspond to the clinical progression of symptoms in Alzheimer's disease (Thal et al., 2002).

The similar topography of fibrillar amyloid-β deposition between typical Alzheimer's disease and PCA groups provides support for the model in which amyloidosis plays a critical role in Alzheimer's disease pathogenesis. Other factors such as neurofibrillary tangles may contribute to the atypical visual clinical presentation (Jack et al., 2002; Csernansky et al., 2004). Indeed, autopsies have reported a greater density of neurofibrillary tangles in PCA than in Alzheimer's disease; these are most notable in the primary visual and visual associative cortex. Autopsies have also found a smaller density of tangles in the hippocampus and subiculum, with a similar density of senile plaques in cortical areas (Tang-Wai et al., 2004).

To conclude, we hypothesize that amyloid-β pathology in PCA occurs at an early phase of the disease, similar to the timing seen in typical Alzheimer's disease, and that the clinical presentation of PCA may result from an interaction with tau-pathology. Because PCA is similar to Alzheimer's disease in terms of amyloid-β pathology but differs in its tau-pathology progression, PCA provides a model to study in vivo the interaction between amyloid and tau pathology, an interaction that is still poorly understood.

11C-PIB-PET and CSF biomarkers have the potential to identify candidate patients with PCA who may benefit from specific therapeutic strategies targeting amyloid-β metabolism. The therapeutic windows during which treatment should be initiated should be discussed with regard to the present data, which provide support for early therapeutic interventions.


French agence Nationale de la Recherche (ANR) under reference ANR-07-LVIE-002-01, French Fondation Nationale de Gerontologie and MEDIAPART; ‘Fondation pour la Recherche Médicale’ (to L.C.dS.). During the two last years, Dr L.C.dS. has collaborated with the pharmaceutical company Lundbeck; European Federation of Neurological Societies (EFNS to Dr O.U.). Mr F.C., Dr M.-O.H., Dr O.U., Dr R.M., Dr F.L., Dr O.C., Ms D.S. and Mrs V.H.-B. report no conflict of interest. During the two last years, Dr M.C. and Pr S.L. have collaborated with the pharmaceutical company EISAI. During the two last years, Pr B.D. has collaborated with the pharmaceutical companies EISAI, Novartis, Roche, Bristol-Mayer-Squib, Servier. During the two last years, Dr M.B. has collaborated with the pharmaceutical company IPSEN-BEAUFOUR. During the two last years, Dr M.S. has collaborated with the pharmaceutical companies EISAI, Novartis, Pfizer, Lundbeck.

Supplementary material

Supplementary material is available at Brain online.


We are greatly indebted to the chemical/radiopharmaceutical and nursing staff of Service Hospitalier Frédéric Joliot for the synthesis of the 11C-PIB and patient management, respectively.


  • *These authors contributed equally to this work.

11C-labelled Pittsburgh compound-B
posterior cortical atrophy


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