- Email: [email protected]
Consequences of beta-amyloid immunotherapy for Alzheimer's disease on neurons in the human cerebral cortex
P284
Poster Presentations: P1
Background: Neuroinflammation, manifested by activation of microglia, is an important component of Alzheimer’s disease (AD) pathology with evidence to suggest that it is both a reaction to the disease process and a contributor to neuronal damage, promotingdisease progression. In this study, we have explored in detail the inflammatory processes in the human AD brain and compared the results with those obtained from patients following active Ab42 immunisation (Elan Pharmaceuticals, AN1792). Methods: We studied multiple brain regions in post-mortem tissue from 28 non-immunised AD patients and 11 AD patients immunised against Ab42 (up to 9 years prior to study). The antigen load was quantified in sections immunolabelled for microglial ionised calcium-binding adaptor molecule 1 (Iba-1), the lysosome marker CD68, macrophage scavenger receptor A (MSR-A), Fcg receptors I (CD64) and II (CD32), IgG, complement C1q and T lymphocytes, and compared to the amount of Ab and phospho-tau pathology. Results: The levels of CD68, MSR-A, CD64, CD32 loads and the number of MSR-A-positive plaque-related clusters were significantly lower in immunised AD than non-immunised cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. In non-immunized AD controls, Ab42 related inversely to CD32 and Iba-1, while phospho-tau was associated with all microglial markers, IgG, C1q and the total number of T cells. In immunised AD cases, Ab42 load related directly to MSR-A-positive clusters, and inversely to C1q. Conclusions: Our findings indicate that different microglial populations coexist in the AD brain and the local inflammatory response may provide an important link between Ab and tau pathology. After immunisation, the microglial functional state is altered in association with reduced Ab and tau pathology. The results suggest that, in the long term, Ab immunotherapy results in down-regulation of microglial activation and potentially reduces the inflammation-mediated component of neurodegeneration of AD.
P1-345
CONSEQUENCES OF BETA-AMYLOID IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE ON NEURONS IN THE HUMAN CEREBRAL CORTEX
Delphine Boche1, Jay Amin1, Franc¸ois Mouton-Liger2, Mariam Nasser1, Seth Love3, Francoise Gray4, Ruth Pickering1, James Nicoll1, Clive Holmes1, Jacques Hugon5, Claire Paquet6, 1University of Southampton, Southampton, United Kingdom; 2INSERM-APHP, Paris, France; 3Univeristy of Bristol, Bristol, United Kingdom; 4Hospital AP-HP University of Paris 7, Paris, France; 5University of Paris VII, Paris, France; 6 University of Paris VII, Paris, France. Contact e-mail: [email protected]. uk Background: Alzheimer’s disease (AD) patients in Ab immunotherapy trials have demonstrated amyloid plaque removal but with little evidence of slowed cognitive decline. We have explored the consequences of immunotherapy on neuronal density and the morphology of neuronal processes. Methods: 11 immunised AD patients (iAD) (Elan Pharmaceuticals, AN1792) were compared to 28 non-immunised AD patients (cAD) as controls. Immunohistochemistry on sections of cortex from frontal, temporal and parietal lobes was performed for: neuron-specific nuclear antigen (NeuN), neurofilament (NFP) and pPKR (phosphorylated pro-apoptotic kinase detected in degenerating neurons). Status spongiosus (neuropil degeneration) was assessed in haematoxylin-and eosin-stained sections. We quantified NFP and pPKR labelling as load (%), the percentage area of cortex showing status spongiosus, NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance (m m). Data were corrected for age, gender, duration of dementia and APOE genotype. Results: Our data show in the iAD compared to the cAD cases: a significantly higher degree of spongiosus (53.3 vs 48.6, P ¼ 0.013), fewer NeuN-positive neurons/field (66.8 vs 73.7, P ¼ 0.036), lower curvature of neuronal processes (1.13 vs 1.23, P < .001), a trends towards a lower pPKR load (0.08 vs 0.16, P ¼ 0.070) and no-significant change in mean interneuronal distance (713.6 vs 705.2, P ¼ 0.370). Conclusions: After immunisation, there is evidence of enhanced neuronal damage in the form of exacerbated status spongiosus and
a lower density of neurons. Remaining neurons seem "healthier" (less curvature of neuronal processes, less pPKR). The data raise the possibility that A b immunisation may accelerate the removal of neurons damaged by AD and are consistent with the report of increased cerebral atrophy detected with MRI.
P1-346
DISEASE PROGRESSION MODELING OF BAPINEUZUMAB UTILIZING ALZHEIMER’S DISABILITY ASSESSMENT FOR DEMENTIA SCORES
Mahesh Samtani1, Steven Xu2, O. J. Adedokun3, Kaori Ito4, Brian Corrigan5, Sangeeta Raje6, Robert H. Brashear7, Scot Styren8, Chuanpu Hu3, Ming Lu9, 1Johnson and Johnson, Raritan, New Jersey, United States; 2Janssen R&D, Raritan, New Jersey, United States; 3Janssen R&D, Spring House, Pennsylvania, United States; 4Pfizer Inc, New London, Connecticut, United States; 5Pfizer Inc, New London, Connecticut, United States; 6Pfizer Inc, Collegeville, Pennsylvania, United States; 7Janssen Alzheimer Immunotherapy, South San Francisco, California, United States; 8 Pfizer Inc, Groton, Connecticut, United States; 9Janssen Research & Development, Spring House, Pennsylvania, United States. Contact e-mail: [email protected] Background: Bapineuzumab was investigated as a disease-modifying therapy for the treatment of mild to moderate AD. Study 301 and Study 302 were randomized, double blind, placebo-controlled Phase 3 studies that were conducted to evaluate the efficacy and safety of bapineuzumab in patients with mild to moderate AD in apolipoprotein E, E4 allele (APOE-ε4) noncarriers and APOE-ε4 carriers respectively. Modeling the longitudinal changes in disease progression as measured by DAD scores and evaluating the impact of bapineuzumab on disease progression were the primary goals of this analysis. Methods: A population pharmacodynamic (PD) model was developed for Disability Assessment for Dementia (DAD) using pooled data obtained from Studies 301 and 302. The population PD model was applied to determine estimates of bapineuzumab PD parameters in these populations and to identify factors, such as demographics or baseline characteristics, which could contribute to the variability in disease progression rate and baseline disease status. Results: A beta regression model best described the disease progression as measured by DAD scores in patients with mild to moderate AD. The placebo effect on DAD in the AD population was not statistically significant. Baseline disease status, age, memantine use, and years since disease onset(YSO) had significant effects on baseline DAD scores, while use of AD concomitant medications (memantine or acetylcholinesterase inhibitors), baseline disease status (mild AD versus moderate AD), and YSO had significant effects on the disease progression as measured by DAD scores. The treatment effect (ie, bapineuzumab versus placebo) on disease progression as measured by DAD scores was not statistically significant, consistent with the lack of clinical efficacy observed in the statistical analyses of both studies. However, the progression of DAD tended to decrease with increase in bapineuzumab exposure. The exposure-response relationship was more pronounced in patients with mild AD, whereas this relationship was similar in APOE-ε4 carriers and noncarriers. Conclusions: This analysis suggested a possible effect of bapineuzumab exposure on DAD progression. Further confirmation of the exposure-response relationship will be performed when additional Phase 3 study data become available.
P1-347
INDIVIDUALS WITH ALZHEIMER’S DISEASE EXHIBIT A HIGH PREVALENCE OF UNDIAGNOSED IMPAIRED GLUCOSE TOLERANCE AND TYPE 2 DIABETES MELLITUS
Raymond Turner1, Suzanne Craft2, Paul Aisen3, 1Georgetown University, Washington, D.C., United States; 2Stitch Center on Aging, Winston-Salem, North Carolina, United States; 3UCSD, La Jolla, California, United States. Contact e-mail: [email protected]
Poster Presentations: P1
Background: Neuroinflammation, manifested by activation of microglia, is an important component of Alzheimer’s disease (AD) pathology with evidence to suggest that it is both a reaction to the disease process and a contributor to neuronal damage, promotingdisease progression. In this study, we have explored in detail the inflammatory processes in the human AD brain and compared the results with those obtained from patients following active Ab42 immunisation (Elan Pharmaceuticals, AN1792). Methods: We studied multiple brain regions in post-mortem tissue from 28 non-immunised AD patients and 11 AD patients immunised against Ab42 (up to 9 years prior to study). The antigen load was quantified in sections immunolabelled for microglial ionised calcium-binding adaptor molecule 1 (Iba-1), the lysosome marker CD68, macrophage scavenger receptor A (MSR-A), Fcg receptors I (CD64) and II (CD32), IgG, complement C1q and T lymphocytes, and compared to the amount of Ab and phospho-tau pathology. Results: The levels of CD68, MSR-A, CD64, CD32 loads and the number of MSR-A-positive plaque-related clusters were significantly lower in immunised AD than non-immunised cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. In non-immunized AD controls, Ab42 related inversely to CD32 and Iba-1, while phospho-tau was associated with all microglial markers, IgG, C1q and the total number of T cells. In immunised AD cases, Ab42 load related directly to MSR-A-positive clusters, and inversely to C1q. Conclusions: Our findings indicate that different microglial populations coexist in the AD brain and the local inflammatory response may provide an important link between Ab and tau pathology. After immunisation, the microglial functional state is altered in association with reduced Ab and tau pathology. The results suggest that, in the long term, Ab immunotherapy results in down-regulation of microglial activation and potentially reduces the inflammation-mediated component of neurodegeneration of AD.
P1-345
CONSEQUENCES OF BETA-AMYLOID IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE ON NEURONS IN THE HUMAN CEREBRAL CORTEX
Delphine Boche1, Jay Amin1, Franc¸ois Mouton-Liger2, Mariam Nasser1, Seth Love3, Francoise Gray4, Ruth Pickering1, James Nicoll1, Clive Holmes1, Jacques Hugon5, Claire Paquet6, 1University of Southampton, Southampton, United Kingdom; 2INSERM-APHP, Paris, France; 3Univeristy of Bristol, Bristol, United Kingdom; 4Hospital AP-HP University of Paris 7, Paris, France; 5University of Paris VII, Paris, France; 6 University of Paris VII, Paris, France. Contact e-mail: [email protected]. uk Background: Alzheimer’s disease (AD) patients in Ab immunotherapy trials have demonstrated amyloid plaque removal but with little evidence of slowed cognitive decline. We have explored the consequences of immunotherapy on neuronal density and the morphology of neuronal processes. Methods: 11 immunised AD patients (iAD) (Elan Pharmaceuticals, AN1792) were compared to 28 non-immunised AD patients (cAD) as controls. Immunohistochemistry on sections of cortex from frontal, temporal and parietal lobes was performed for: neuron-specific nuclear antigen (NeuN), neurofilament (NFP) and pPKR (phosphorylated pro-apoptotic kinase detected in degenerating neurons). Status spongiosus (neuropil degeneration) was assessed in haematoxylin-and eosin-stained sections. We quantified NFP and pPKR labelling as load (%), the percentage area of cortex showing status spongiosus, NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance (m m). Data were corrected for age, gender, duration of dementia and APOE genotype. Results: Our data show in the iAD compared to the cAD cases: a significantly higher degree of spongiosus (53.3 vs 48.6, P ¼ 0.013), fewer NeuN-positive neurons/field (66.8 vs 73.7, P ¼ 0.036), lower curvature of neuronal processes (1.13 vs 1.23, P < .001), a trends towards a lower pPKR load (0.08 vs 0.16, P ¼ 0.070) and no-significant change in mean interneuronal distance (713.6 vs 705.2, P ¼ 0.370). Conclusions: After immunisation, there is evidence of enhanced neuronal damage in the form of exacerbated status spongiosus and
a lower density of neurons. Remaining neurons seem "healthier" (less curvature of neuronal processes, less pPKR). The data raise the possibility that A b immunisation may accelerate the removal of neurons damaged by AD and are consistent with the report of increased cerebral atrophy detected with MRI.
P1-346
DISEASE PROGRESSION MODELING OF BAPINEUZUMAB UTILIZING ALZHEIMER’S DISABILITY ASSESSMENT FOR DEMENTIA SCORES
Mahesh Samtani1, Steven Xu2, O. J. Adedokun3, Kaori Ito4, Brian Corrigan5, Sangeeta Raje6, Robert H. Brashear7, Scot Styren8, Chuanpu Hu3, Ming Lu9, 1Johnson and Johnson, Raritan, New Jersey, United States; 2Janssen R&D, Raritan, New Jersey, United States; 3Janssen R&D, Spring House, Pennsylvania, United States; 4Pfizer Inc, New London, Connecticut, United States; 5Pfizer Inc, New London, Connecticut, United States; 6Pfizer Inc, Collegeville, Pennsylvania, United States; 7Janssen Alzheimer Immunotherapy, South San Francisco, California, United States; 8 Pfizer Inc, Groton, Connecticut, United States; 9Janssen Research & Development, Spring House, Pennsylvania, United States. Contact e-mail: [email protected] Background: Bapineuzumab was investigated as a disease-modifying therapy for the treatment of mild to moderate AD. Study 301 and Study 302 were randomized, double blind, placebo-controlled Phase 3 studies that were conducted to evaluate the efficacy and safety of bapineuzumab in patients with mild to moderate AD in apolipoprotein E, E4 allele (APOE-ε4) noncarriers and APOE-ε4 carriers respectively. Modeling the longitudinal changes in disease progression as measured by DAD scores and evaluating the impact of bapineuzumab on disease progression were the primary goals of this analysis. Methods: A population pharmacodynamic (PD) model was developed for Disability Assessment for Dementia (DAD) using pooled data obtained from Studies 301 and 302. The population PD model was applied to determine estimates of bapineuzumab PD parameters in these populations and to identify factors, such as demographics or baseline characteristics, which could contribute to the variability in disease progression rate and baseline disease status. Results: A beta regression model best described the disease progression as measured by DAD scores in patients with mild to moderate AD. The placebo effect on DAD in the AD population was not statistically significant. Baseline disease status, age, memantine use, and years since disease onset(YSO) had significant effects on baseline DAD scores, while use of AD concomitant medications (memantine or acetylcholinesterase inhibitors), baseline disease status (mild AD versus moderate AD), and YSO had significant effects on the disease progression as measured by DAD scores. The treatment effect (ie, bapineuzumab versus placebo) on disease progression as measured by DAD scores was not statistically significant, consistent with the lack of clinical efficacy observed in the statistical analyses of both studies. However, the progression of DAD tended to decrease with increase in bapineuzumab exposure. The exposure-response relationship was more pronounced in patients with mild AD, whereas this relationship was similar in APOE-ε4 carriers and noncarriers. Conclusions: This analysis suggested a possible effect of bapineuzumab exposure on DAD progression. Further confirmation of the exposure-response relationship will be performed when additional Phase 3 study data become available.
P1-347
INDIVIDUALS WITH ALZHEIMER’S DISEASE EXHIBIT A HIGH PREVALENCE OF UNDIAGNOSED IMPAIRED GLUCOSE TOLERANCE AND TYPE 2 DIABETES MELLITUS
Raymond Turner1, Suzanne Craft2, Paul Aisen3, 1Georgetown University, Washington, D.C., United States; 2Stitch Center on Aging, Winston-Salem, North Carolina, United States; 3UCSD, La Jolla, California, United States. Contact e-mail: [email protected]