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

Liu, Enchi; Schmidt, Mark E.; Margolin, Richard; Sperling, Reisa A.; Koeppe, Robert A.; Mason, N. Scott; Klunk, William E.; Mathis, Chester A.; Salloway, Stephen; Fox, Nick C.; Hill, Derek L. G.; Les, Andrea S.; Collins, Peter; Gregg, Keith M.; Di, Jianing; Lü, Yuan; Tudor, Iulia Cristina; Wyman, Bradley T.; Booth, Kevin; Broome, Stephanie; Yuen, Eric; Grundman, Michael; Brashear, H. Robert

doi:10.1212/wnl.0000000000001877

Cited by 137 publications

(101 citation statements)

References 25 publications

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“…Although the lack of cognitive improvement in the Gammagard trials is discouraging, there is a growing consensus that AD will likely have to be tackled during the prodromal phase with primary or secondary prevention trials, as even Aβ-targeting antibodies have failed to improve cognition in phase III trials (44,45). It is therefore quite possible that Gammagard or other IgG formulations, perhaps combined with transient permeabilization of the BBB through focused ultrasound, might provide increased benefit if tested in prodromal AD.…”

Section: Discussionmentioning

confidence: 99%

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

331

287

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The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptiveinnate immunity cross talk and accelerated disease progression.is the leading cause of age-related neurodegeneration, affecting over 5.2 million people in the United States alone (1). Pathologically, AD is characterized by two hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles, that are accompanied by neuroinflammation, including microgliosis, elevated cytokine production, and activation of complement pathways (2-5). Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs. 6-8). However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9, 10). Although much of the data implicating microglia in AD has come from neuropathological investigation, recent genome-wide association studies have provided the first genetic evidence (to our knowledge) linking microglia dysfunction to AD, with the discovery of risk polymorphisms in several immune system genes: CR1, TREM2, CD33, HLA-DRB5, MS4A6A, and ABCA7 (8,(11)(12)(13)(14)(15).In contrast to the field's increasing understanding of the role of innate immunity in AD, comparatively little is known about whether the adaptive immune system might also influence AD. Those studies that have examined these peripheral populations have largely focused on questions about their potential as biomarkers or their role in active Aβ immunization (3, 16). However, the adaptive and innate immune systems rarely fu...

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Section: Discussionmentioning

confidence: 99%

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

331

287

View full text Add to dashboard Cite

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“…Among many other applications, amyloid-b imaging has been incorporated into diagnostic criteria for various stages of the disease (Albert et al, 2011;McKhann et al, 2011;Sperling et al, 2011;Dubois et al, 2014), has substantial impact on clinical decision-making (Ossenkoppele et al, 2013a;Sanchez-Juan et al, 2014) and patient management plans (Schipke et al, 2012;Grundman et al, 2013), and has shown potential as a surrogate outcome measure in clinical trials tailored to reduce cerebral amyloid-b plaque burden (Salloway et al, 2014;Liu et al, 2015). A yet unresolved issue after a decade of amyloid-b imaging research, however, is the disconnection between the diffuse distribution of amyloid-b pathology throughout the neocortex (Rabinovici et al, 2010;Wolk et al, 2012;Lehmann et al, 2013;Jung et al, 2015) and the selective patterns of brain atrophy and glucose hypometabolism that strongly correlate with clinical symptoms (Rabinovici et al, 2010;Ridgway et al, 2012;Lehmann et al, 2013;Madhavan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease

Ossenkoppele

Schonhaut

Schöll

et al. 2016

Brain

902

117

923

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The advent of the positron emission tomography tracer 18 F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-b pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-b-negative cognitively normal individuals, who underwent 18 F-AV1451 (tau), 11 C-PiB (amyloid-b) and 18 F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P 5 0.05 family-wise error corrected) showed that 18 F-AV1451 and thresholded at P 5 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater 18 F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased 18 F-AV1451 in the medial temporal lobe. APOE e4 carriers showed greater temporal and parietal 18 F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater 18 F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left 4 right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-b imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease. Keywords: Alzheimer's disease; tau; AV1451 PET; cognition; APOE Abbreviations: AI = asymmetry index; DVR = distribution volume ratio; MMSE = Mini-Mental State Examination; PCA = posterior cortical atrophy; PiB = Pittsburgh compound B; PPA = primary progressive aphasia; SUVR = standardized uptake value ratio

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“…Two additional trials with the same structure of ApoE 4 carriers and noncarriers were conducted in multiple countries with a similar lack of functional effectiveness, but without adverse effects [26]. Other studies have reported improved brain volume in imaging and plaque reduction in patients treated with bapineuzumab [27,28], but the relevance of these observations is not clear since functional studies have reported no significant benefits.…”

Section: First-generation Anti-aβ42 Antibodiesmentioning

confidence: 99%

Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target

Wang¹,

Yan

Hong³

et al. 2017

Neurodegener Dis

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Background: Available drugs for the global Alzheimer disease (AD) epidemic only treat the symptoms without modifying disease progression. Accumulating evidence supports amyloid-β42 (Aβ42)as the key triggering agent in AD, making it the ideal target for disease-modifying therapies. Preclinical studies provided extensive support for passive Aβ42 immunotherapy, leading to human clinical trials with different antibodies. Objective: Examine the status of clinical trials for passive immunotherapy against Aβ42. Methods: We performed a thorough literature review of passive Aβ42 immunotherapy. Results: Ten anti-Aβ42 antibodies targeting lineal or conformational epitopes have been tested in clinical trials. Antibody engineering and appropriate dosing have overcome undesired side effects, leading to increased safety profiles. Unfortunately, few trials have shown cognitive protection, leading to legitimate questions about the utility of Aβ42 as an AD target. There is still hope that solanezumab, aducanumab, and other ongoing trials will identify antibodies, patient subpopulations, and administration protocols, with consistent clinical benefits. Conclusions: Despite the overall disappointing results, there is still hope that Aβ immunotherapy in presymptomatic patients will prevent neuronal loss and provide significant clinical benefits that can be applied to larger populations as preventive therapies. Advances with other targets may soon provide additional therapeutic options for AD with increased efficacy.

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

Cited by 137 publications

References 25 publications

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease

Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target

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

Cited by 137 publications

References 25 publications

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease

Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target

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Product

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