Progression of Cerebral Amyloid Load Is Associated with the Apolipoprotein E ε4 Genotype in Alzheimer's Disease

Grimmer, Timo; Tholen, Susanne; Yousefi, Behrooz H.; Alexopoulos, Panagiotis; Förschler, Annette; Förstl, Hans; Henriksen, Gjermund; Klunk, William E.; Mathis, Chester A.; Perneczky, Robert; Sorg, Christian; Kurz, Alexander; Drzezga, Alexander

doi:10.1016/j.biopsych.2010.05.013

Cited by 100 publications

(92 citation statements)

References 38 publications

(50 reference statements)

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“…By contrast, the bilateral hippocampus, caudate nucleus, thalamus, amygdala, and parahippocampal gyri had the smallest slope and the lowest AAR. Our findings are well in line with those of Grimmer et al (23), who examined regional progression of Ab in Alzheimer dementia using PET with Pittsburgh compound B (23). As in our study, they found that regions of the frontal lobe followed by those of the parietal lobe showed the highest accumulation rate, whereas the temporal lobe appeared to have the lowest rate across the neocortex.…”

Section: Discussionsupporting

confidence: 82%

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Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET

Guo

Brendel²,

Grimmer

et al. 2016

J Nucl Med

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Knowledge about spatial and temporal patterns of b-amyloid (Ab) accumulation is essential for understanding Alzheimer disease (AD) and for design of antiamyloid drug trials. Here, we tested whether the regional pattern of longitudinal Ab accumulation can be predicted by baseline amyloid PET. Methods: Baseline and 2-y followup 18 F-florbetapir PET data from 58 patients with incipient and manifest dementia due to AD were analyzed. With the determination of how fast amyloid deposits in a given region relative to the wholebrain gray matter, a pseudotemporal accumulation rate for each region was calculated. The actual accumulation rate of 18 F-florbetapir was calculated from follow-up data. Results: Pseudotemporal measurements from baseline PET data explained 87% (P , 0.001) of the variance in longitudinal accumulation rate across 62 regions. The method accurately predicted the top 10 fast and slow accumulating regions. Conclusion: Pseudotemporal analysis of baseline PET images is capable of predicting the regional pattern of longitudinal Ab accumulation in AD at a group level. This approach may be useful in exploring spatial patterns of Ab accumulation in other amyloidassociated disorders such as Lewy body disease and atypical forms of AD. In addition, the method allows identification of brain regions with a high accumulation rate of Ab, which are of particular interest for antiamyloid clinical trials.

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Section: Discussionsupporting

confidence: 82%

“…As in our study, they found that regions of the frontal lobe followed by those of the parietal lobe showed the highest accumulation rate, whereas the temporal lobe appeared to have the lowest rate across the neocortex. Further, most of the FARs accumulated Ab faster in the left hemisphere (23). The same order of accumulation rate (frontal .…”

Section: Discussionmentioning

confidence: 63%

Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET

Guo

Brendel²,

Grimmer

et al. 2016

J Nucl Med

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“…Among placebo participants with baseline GCA $1.35, carriers showed an increase in 11 C-PiB signal over the course of the study, whereas noncarriers did not. Grimmer et al 17 also found differences by APOE e4 genotype in the progression of the cortical 11 C-PiB-PET signal in participants with AD over a 2-year interval. This finding may suggest that APOE e4 has a sustained influence on Ab Figure 2 Model-estimated effect of bapineuzumab on Ab burden in carriers, noncarriers, pooled studies, and by disease severity accumulation and not just on the timing of its initiation and could also have implications regarding the use of amyloid PET in detecting treatment effects targeting Ab deposition.…”

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confidence: 92%

Amyloid-β ¹¹ C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

Liu¹,

Schmidt²,

Margolin³

et al. 2015

Neurology

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Objective: To evaluate the effects of bapineuzumab on brain b-amyloid (Ab) burden using 11 C-Pittsburgh compound B ( 11 C-PiB)-PET.Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE e4 carriers and noncarriers,were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Ab monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Ab over 71 weeks using an 11 C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. Bapineuzumab, a humanized monoclonal antibody targeting the N-terminus of b-amyloid (Ab), was recently evaluated in phase 3 trials for the treatment of mild to moderate Alzheimer disease (AD) dementia. As part of those investigations, brain volumetric MRI, brain amyloid PET imaging, and CSF sampling were performed in biomarker substudies. The primary aim of the substudies was to assess the pharmacologic effects of bapineuzumab on AD CNS biomarkers. The PET substudy used 11 C-Pittsburgh compound B ( 11 C-PiB)-PET as a measure of brain fibrillar Ab.1 Differences in the incidence of amyloid-related imaging abnormalities (ARIA) and potential efficacy signals had been seen between participants treated with bapineuzumab who were APOE e4 carriers and noncarriers in phase 2 studies 2-4 ; therefore, separate clinical trials for APOE e4 carriers (Study 302) and noncarriers (Study 301) were conducted in phase 3. The primary clinical and biomarker endpoint results of these trials were recently All authors contributed equally to this work.

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“…The association of APOE4 with AD risk was first described in 1993 (6,7), leading to research efforts focused on the effects of the APOE genotype on plaque burden and the structural relationship between apoE and amyloid. IHC analysis demonstrates that plaque deposition is greater with APOE4 compared with APOE3 in AD and nondemented controls (8,9) and that a higher proportion of A␤ within a plaque is associated with apoE4 than with apoE3 (10). Biochemical analysis confirms that the levels of apoE and A␤ are also higher with APOE4 compared with APOE3 in the insoluble extraction fraction from brains of FAD-Tg mice (11).…”

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confidence: 99%

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

Tai

Bilousova

Jungbauer

et al. 2013

Journal of Biological Chemistry

137

146

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Background: An ELISA was developed to determine the role of apoE/A␤ on soluble A␤ accumulation. Results: In AD transgenic mouse brain and human synaptosomes and CSF, levels of soluble apoE/A␤ are lower and oligomeric A␤ levels are higher with APOE4 and AD. Conclusion: Isoform-specific apoE/A␤ levels modulate soluble oligomeric A␤ levels. Significance: ApoE/A␤ and oligomeric A␤ represent a mechanistic approach to AD biomarkers.

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Progression of Cerebral Amyloid Load Is Associated with the Apolipoprotein E ε4 Genotype in Alzheimer's Disease

Cited by 100 publications

References 38 publications

Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET

Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET

Amyloid-β ¹¹ C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

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Progression of Cerebral Amyloid Load Is Associated with the Apolipoprotein E ε4 Genotype in Alzheimer's Disease

Cited by 100 publications

References 38 publications

Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET

Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET

Amyloid-β 11 C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

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Amyloid-β ¹¹ C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials