Do cerebellar plaques influence 18F-florbetaben amyloid PET scan quantification?

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Podium Presentations: Wednesday, July 22, 2015

species. We, therefore, investigated the region specific correlation between in vivo [11C]PiB retention and the postmortem burden of neuritic plaques (NPs), diffuse plaques (DPs) or cerebral amyloid angiopathy (CAA). Methods: A total of 33 subjects with PiB-PET during life and postmortem neuropathologic examination (31 with dementia and 2 with MCI, mean age at PET¼66.768.1, interval from PET to autopsy 3.261.8 years) were assessed. PiB SUVR (gray cerebellum reference) and post-mortem Ab burden were analyzed in five cortical ROIs: anterior cingulate, middle frontal, inferior temporal, angular and calcarine. PiB SUVRs were extracted in template space using customized ROIs matching regions sampled at autopsy. NP were quantified using CERAD, and DP/ CAA and were classified by the pathologist as: none to sparse and moderate to frequent. PET to autopsy correlations were examined using multi-linear regression. Results: The overall prevalence of pathology was 59.5% none-sparse/40.5% moderate-frequent for NP, 52.8%/47.2% for DP and 82.2%/17.8% for CAA. When examined separately (adjusting for PET-autopsy interval), moderate to severe NP (b¼0.411w0.863, p<0.05) and DP (b¼0.264w0.879, p<0.05) each correlated with PiB SUVR in all regions, while moderate to severe CAA predicted high PiB SUVR in the anterior cingulate and calcarine regions (b¼0.393/0.332, p¼0.004/0.004). When NP and DP or CAA were included in the same model, moderate to severe NP correlated with PiB SUVR in all regions (b¼0.362w0.946, p<0.05), whereas DP in the anterior cingulate (b¼0.486, p¼0.024) independently correlated with PiB SUVR after controlling for NP. The significance of CAA disappeared after controlling for NP. Tests for trends across dose dependent amyloid burdens (none, sparse, moderate and frequent) showed that increased NP burdens in all regions and DP in the anterior cingulate and angular regions associated with high PiB SUVR. Conclusions: In a dementia clinic population, regional PiB signal was dominated by NP, though DP contributed to signal in some regions. These findings have implications for clinical and research applications of amyloid PET. O4-08-02

IMPACT OF MORPHOLOGICALLY DISTINCT AMYLOID ß (Aß) DEPOSITS ON 18F-FLORBETABEN (FBB) PET SCANS

James B. Leverenz1, Osama Sabri2, Ana M. Catafau3, Henryk Barthel2, John Seibyl4, Bernardino Ghetti5, James W. Ironside6, Santiago Bullich3, Walter J. Schulz-Schaeffer7, Anja Hoffman8, 1Cleveland Clinic Neurological Institute, Cleveland, OH, USA; 2University of Leipzig, Leipzig, Germany; 3Piramal Imaging GmbH, Berlin, Germany; 4Molecular NeuroImaging, New Haven, CT, USA; 5Indiana University School of Medicine, Indianapolis, IN, USA; 6University of Edinburgh, Edinburgh, Scotland; 7Georg-August University G€ottingen, G€ottingen, Germany; 8 Bayer Pharma AG, Berlin, Germany. Contact e-mail: [email protected]

SUVR¼a0+an3n+ad3d+av3v, where a0, an, ad, avare constants, and n¼NEUR, d¼DIFF and v¼VASC. n, d, and v were assigned two values: 0¼Ab absent; 1¼Ab present. Results: In ROIs with high frequency of Aß (frontal, posterior cingulate), both DIFF (a¼0.32 and 0.42) and NEUR (a¼0.27 and 0.21) contributed significantly to the SUVR. In regions with low frequency of Aß (occipital, anterior cingulate), only DIFF contributed significantly to the SUVR (a¼0.24 and 0.55). Presence of VASC contributed significantly to the SUVR only in the occipital region (a¼0.13). Conclusions: There was a significant impact of DIFF and VASC on FBB SUVR in brain regions characterized by low Aß load. These results underline the importance of measuring the topographic distribution of Aß aggregates and suggest the potential utility of FBB in detecting both DIFF and VASC Aß deposits. Table Coefficient values from the fitted models to each regional SUVR for each type of amyloid deposition (p values)

Region

adiffuse

aneuritic

Frontal Posterior cingulate Occipital Anterior cingulated

0.32 (0.001)* 0.42 (<10-4)* 0.24 (0.0001)* 0.55 (<10-4)*

0.27 (0.002)* 0.09 (0.22) 0.21 (0.01)* -0.03 (0.77) 0.10 (0.07) 0.13 (0.01)* 0.09 (0.37) -0.02 (0.85)

avascular

*Statistically significant (p<0.05). Coefficient values>0 indicate contribution to SUVR O4-08-03

DO CEREBELLAR PLAQUES INFLUENCE 18 F-FLORBETABEN AMYLOID PET SCAN QUANTIFICATION?

Ana M. Catafau1, Santiago Bullich1, John Seibyl2, Henryk Barthel3, Bernardino Ghetti4, James B. Leverenz5, James W. Ironside6, Walter J. Schulz-Schaeffer7, Anja Hoffman8, Osama Sabri3, 1Piramal Imaging GmbH, Berlin, Germany; 2Molecular NeuroImaging, New Haven, CT, USA; 3University of Leipzig, Leipzig, Germany; 4Indiana University School of Medicine, Indianapolis, IN, USA; 5Cleveland Clinic Neurological Institute, Cleveland, OH, USA; 6University of Edinburgh, Edinburgh, Scotland; 7Georg-August University G€ottingen, G€ottingen, Germany; 8Bayer Pharma AG, Berlin, Germany. Contact e-mail: [email protected] Background: Standardized uptake value ratios (SUVR) are commonly used for quantification of 18F-Florbetaben (FBB) scans. Cerebellar gray matter is used as the reference region for Table ANOVA

Cerebellar plaques Region (n)

Background: Morphologically distinct Aß deposits, such as diffuse

SUVR (full sample)

or neuritic Aß plaques (DIFF, NEUR), and vascular Aß (VASC) may be present in Alzheimer’s disease (AD). FBB has been validated as a biomarker of NEUR. It was the aim of this project to investigate the impact of the different forms of Ab deposits on FBB PET scans. Methods: Brain tissue was collected from 87 end-of-life patients (64 AD patients) who underwent a FBB PET scan before death. Aß immunohistochemistry (IHC) was used for assessment of VASC. Aß IHC and Bielschowsky silver stain were used for assessment of NEUR and DIFF in frontal, occipital, anterior cingulate and posterior cingulate cortices. Cortical SUVRs were obtained in all ROIs using cerebellar grey matter as reference region. A linear regression model was fitted for each ROI as:

Frontal (83) Occipital (82) Ant. Cing (82) Post. Cing (82) SUVR (moderate or frequent Ab plaques) Frontal (47) Occipital (44) Ant. Cing (26) Post. Cing (36)

Absent

Sparse

Moderate

p-value

1.36 6 0.35 1.44 6 0.21 1.38 6 0.40 1.59 6 0.38

1.70 6 0.33 1.66 6 0.24 1.74 6 0.38 1.87 6 0.37

1.82 6 0.29 1.69 6 0.26 1.86 6 0.31 1.86 6 0.24

<104 0.0001 0.0001 0.004

1.64 6 0.30 1.64 6 0.20 1.73 6 0.39 1.93 6 0.37

1.77 6 0.28 1.68 6 0.23 1.77 6 0.36 1.95 6 0.34

1.73 6 0.24 1.69 6 0.26 1.74 6 0.18 1.7960.20

0.39 0.84 0.97 0.69

Podium Presentations: Wednesday, July 22, 2015

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ques were found in 33 samples, and moderate diffuse plaques in 5. Subjects with higher cerebellar plaque loads showed higher cortical Ab loads and standardized uptake values. Thus, cortical SUVRs significantly increased with cerebellar plaque load (table, figure 1). However, in cortical regions with moderate or frequent Ab plaques no significant SUVR differences were found among brains showing different cerebellar plaque loads (table, figure 2). Conclusions: In brains with higher cerebral cortical Ab loads, cerebellar plaques were found in 47% of cases, mostly as sparse diffuse plaques (40%). However, the presence of cerebellar plaques did not influence the SUVRs in these subjects with moderate or frequent cortical Ab. Therefore, the effect of cerebellar plaques in FBB SUVR appears to be negligible even in advanced stages of AD with a high cortical Ab load.

O4-08-04

Figure 1.

quantification. However, cerebellar plaques may be present in Alzheimer disease (AD). The aim of this study was to assess the influence of cerebellar plaques in FBB SUVR, when using cerebellar gray matter as the reference. Methods: Neuropathological assessment of cerebral (frontal, occipital, anterior and posterior cingulate) cortex and cerebellar cortex tissue from 87 end of life patients (64 AD, 14 other dementia, 9 non-demented aged volunteers; 80.4610.2 yrs) who underwent a FBB PET before death was performed using the Bielschowsky silver stain and Amyloid b (Ab) immunohistochemistry to quantify neuritic/cored and diffuse plaques, as absent, sparse, moderate and frequent. Mean cortical SUVRs were compared among brains with different cerebellar plaque loads. Results: None from the 83 evaluable cerebellar samples showed frequent cerebellar plaques. Only 1 sample showed both sparse neuritic/cored and sparse diffuse plaques. Sparse diffuse pla-

Figure 2.

HETEROGENEOUS HISTOPATHOLOGY OF CAARELATED CORTICAL MICROBLEEDS

Susanne J. van Veluw1, Geert Jan Biessels1, Catharina J.M. Klijn1, Annemieke Rozemuller2, 1University Medical Center Utrecht, Utrecht, Netherlands; 2VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: Cerebral microbleeds (MBs) have received an increasing interest over the past years, because of their association with cerebrovascular disease and dementia. Strictly lobar MBs may be indicative of cerebral amyloid angiopathy (CAA). However, the exact histopathology of CAA related MBs remains poorly understood. It has been suggested that MBs could be related to both hemorrhagic and ischemic injury. We performed a high resolution 7T post-mortem MRI study with histopathological correlation of observed MBs in patients with pathologically proven severe CAA. Additionally, we assessed cortical microinfarcts on the post-mortem MR images of these cases. Methods: In total fifteen formalin-fixed 10-mm thick coronal brain slices from five patients (mean age 79.665.7 years) with pathologically proven severe CAA were scanned on a whole body 32-channel head coil 7T MRI system. T2- (voxel size 400x400x400mm3), fluid-attenuated inversion recovery (FLAIR) (voxel size 400x400x400mm3), and T2*-weighted (voxel size 180x180x180mm3) images were acquired overnight. The T2- and T2*-weighted images were screened for MBs after which a representative number of MBs was sampled (N¼21) and subjected to histopathology. Sections were stained with H&E, Iron, and Ab. Additionally, cortical microinfarcts were assessed on the post-mortem FLAIR and T2weighted images. Results: In total we identified >300 cortical MBs in four patients, three subcortical MBs in one patient, and one hippocampal MB in one patient. No MBs were observed in the white matter. One patient had no MBs. On histology, nine cortical MBs corresponded to focal or dispersed accumulations of hemosiderin-containing macrophages, without erythrocytes. Two cortical MBs corresponded to erythrocytes, three to fibrinoid necrosis, and one proved to be a cavernoma. All lesions showed a mild to moderate degree of gemistocytic (reactive) astrocytes, which could be indicative of ischemic tissue injury. Thirty-nine cortical microinfarcts were observed on MRI. Conclusions: The main finding of this study is that the underlying histopathology of MR observed cortical MBs in patients with severe CAA is heterogeneous and suggestive of both hemorrhagic and ischemic tissue injury. The observation of cortical microinfarcts on MRI in these cases further supports the idea that CAA involves both hemorrhagic and ischemic processes.