- Email: [email protected]
68 Cerebral microbleeds: identification, prevalence and clinical relevance
S30
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
when there are no symptoms and just signs detected by image or biomarkers. In this context the situation is somewhat more controversial. In the case of the familiar forms of AD, the carriers of the mutation sooner or later will have AD. Trials in these populations, those are rare but can be done due to the collaboration of networks. These populations have a very particular high risk and this will be considered by the regulators as a special case. Populations of elderly patients with high amyloid load without clinical symptoms are under research but not yet an important regulatory target. In particular the issue of safety in this population is of the utmost importance.
68
CEREBRAL MICROBLEEDS: IDENTIFICATION, PREVALENCE AND CLINICAL RELEVANCE
Philip Scheltens, VU University Medical Center, Amsterdam, The Netherlands. Contact e-mail: [email protected] -Lobar microbleeds in patients with Dementia are found to be associated with high amyloid burden -Microbleeds are shown to have different etiologies and associated risk of mortality on the basis of their location in the brain. New terminology for amyloid-related imaging abnormalties (ARIA) and a new cut-off point for microbleeds in participants of amyloid-modifying clinical trials were recently introduced. Susceptibility-weighted imaging showed enhanced sensitivity for detecting microbleeds compared with gradientecho imaging, and may help in future for identifying associations between microbleeds and clinical outcomes. Studies that compared imaging with histopathology of microbleeds suggest that further refinement of imaging techniques is required to accurately detect these lesions.
69
PRECLINICAL AND CLINICAL CONSIDERATIONS FOR ABETA IMMUNOTHERAPY
Dale Schenk, Janssen Alzheimer Immunotherapy, South San Francisco, CA, USA. Contact e-mail: [email protected] Abeta immunotherapy as a potential treatment for Alzheimer’s disease was first described over a decade ago. This approach has been instrumental in better understanding the biological role and pathological effects of both soluble and deposited forms of abeta in animal models and patients suffering from Alzheimer’s disease. Extensive research has suggested that multiple mechanisms are involved in the clearance of abeta from brain by abeta immunotherapy. Recent findings have suggested that the epitope specificity
of an antibody to abeta can have differential biological consequences in vivo. These consequences appear to result in not only differential clearance of various form of abeta, but also downstream changes in synaptic markers as well as differences in protective effects on behavior in animal models of the disease. The molecular basis for these differences likely are a result of the effects of different antibodies binding to abeta differentially thereby inducing changes in the resulting structure of the peptide as revealed by X ray crystallography. Through an understanding of these molecular changes, together with extensive animal model analysis, biomarker investigations and ultimately clinical outcomes, it appears that abeta immunotherapy is leading to a very deep understanding of the role of abeta in Alzheimer’s disease as well as a potentially new approach to treament aimed at the underlying pathology of the disease.
70
AFFITOPE® — BASED VACCINES: RESULTS FROM PHASE I SUPPORT THE FURTHER CLINICAL DEVELOPMENT OF AFFITOPE® AD02
Achim Schneeberger, M. Mandler, F. Mattner, W. Schmidt, AFFiRiS AG, Vienna, Austria. Contact e-mail: [email protected] Based on the notion that cerebral accumulation of certain forms of A (unprocessed as well as N-terminally truncated/modified versions) is central to the pathogenesis of Alzheimer’s disease (AD) and endowed with the knowledge that emerged during clinical testing of the first Alzheimer vaccine, AN1792 (Elan/Wyeth), AFFiRiS introduced a new generation of AD vaccines. Rather than relying on full-length A itself or fragments thereof, AFFITOPE® vaccines use short peptides, mimicking parts of the native A sequence, as their antigenic component. The technology created to identify these peptides, termed AFFITOME®-technology, concomitantly provides the basis for the multi-component safety concept (short antigens preclude activation of encephalitogenic T cells; AFFITOME®-technology controls specificity of antibodies induced) realized in AFFITOPE® vaccines. The AFFiRiS AD immunotherapy program focuses on two targets: AFFITOPEs® AD01 and AD02 (which differ in their peptide sequence) target the native N-terminus of A while AFFITOPE® AD03 addresses N-terminally-truncated and pyroglutamate-modified forms of A. AD03 just finished phase I clinical testing. Phase I testing of AD01 and AD02 was done in parallel, monocenter studies run at two different sites. In each study, 24 patients were vaccinated; 12 received the vaccine with adjuvant and 12 without. Clinical phase I data to the safety of AFFITOPE® AD01, AD02 (and AD03 – as available), spanning a time period of 20⫹ months (AD01/AD02), support the safety concept inherent
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
when there are no symptoms and just signs detected by image or biomarkers. In this context the situation is somewhat more controversial. In the case of the familiar forms of AD, the carriers of the mutation sooner or later will have AD. Trials in these populations, those are rare but can be done due to the collaboration of networks. These populations have a very particular high risk and this will be considered by the regulators as a special case. Populations of elderly patients with high amyloid load without clinical symptoms are under research but not yet an important regulatory target. In particular the issue of safety in this population is of the utmost importance.
68
CEREBRAL MICROBLEEDS: IDENTIFICATION, PREVALENCE AND CLINICAL RELEVANCE
Philip Scheltens, VU University Medical Center, Amsterdam, The Netherlands. Contact e-mail: [email protected] -Lobar microbleeds in patients with Dementia are found to be associated with high amyloid burden -Microbleeds are shown to have different etiologies and associated risk of mortality on the basis of their location in the brain. New terminology for amyloid-related imaging abnormalties (ARIA) and a new cut-off point for microbleeds in participants of amyloid-modifying clinical trials were recently introduced. Susceptibility-weighted imaging showed enhanced sensitivity for detecting microbleeds compared with gradientecho imaging, and may help in future for identifying associations between microbleeds and clinical outcomes. Studies that compared imaging with histopathology of microbleeds suggest that further refinement of imaging techniques is required to accurately detect these lesions.
69
PRECLINICAL AND CLINICAL CONSIDERATIONS FOR ABETA IMMUNOTHERAPY
Dale Schenk, Janssen Alzheimer Immunotherapy, South San Francisco, CA, USA. Contact e-mail: [email protected] Abeta immunotherapy as a potential treatment for Alzheimer’s disease was first described over a decade ago. This approach has been instrumental in better understanding the biological role and pathological effects of both soluble and deposited forms of abeta in animal models and patients suffering from Alzheimer’s disease. Extensive research has suggested that multiple mechanisms are involved in the clearance of abeta from brain by abeta immunotherapy. Recent findings have suggested that the epitope specificity
of an antibody to abeta can have differential biological consequences in vivo. These consequences appear to result in not only differential clearance of various form of abeta, but also downstream changes in synaptic markers as well as differences in protective effects on behavior in animal models of the disease. The molecular basis for these differences likely are a result of the effects of different antibodies binding to abeta differentially thereby inducing changes in the resulting structure of the peptide as revealed by X ray crystallography. Through an understanding of these molecular changes, together with extensive animal model analysis, biomarker investigations and ultimately clinical outcomes, it appears that abeta immunotherapy is leading to a very deep understanding of the role of abeta in Alzheimer’s disease as well as a potentially new approach to treament aimed at the underlying pathology of the disease.
70
AFFITOPE® — BASED VACCINES: RESULTS FROM PHASE I SUPPORT THE FURTHER CLINICAL DEVELOPMENT OF AFFITOPE® AD02
Achim Schneeberger, M. Mandler, F. Mattner, W. Schmidt, AFFiRiS AG, Vienna, Austria. Contact e-mail: [email protected] Based on the notion that cerebral accumulation of certain forms of A (unprocessed as well as N-terminally truncated/modified versions) is central to the pathogenesis of Alzheimer’s disease (AD) and endowed with the knowledge that emerged during clinical testing of the first Alzheimer vaccine, AN1792 (Elan/Wyeth), AFFiRiS introduced a new generation of AD vaccines. Rather than relying on full-length A itself or fragments thereof, AFFITOPE® vaccines use short peptides, mimicking parts of the native A sequence, as their antigenic component. The technology created to identify these peptides, termed AFFITOME®-technology, concomitantly provides the basis for the multi-component safety concept (short antigens preclude activation of encephalitogenic T cells; AFFITOME®-technology controls specificity of antibodies induced) realized in AFFITOPE® vaccines. The AFFiRiS AD immunotherapy program focuses on two targets: AFFITOPEs® AD01 and AD02 (which differ in their peptide sequence) target the native N-terminus of A while AFFITOPE® AD03 addresses N-terminally-truncated and pyroglutamate-modified forms of A. AD03 just finished phase I clinical testing. Phase I testing of AD01 and AD02 was done in parallel, monocenter studies run at two different sites. In each study, 24 patients were vaccinated; 12 received the vaccine with adjuvant and 12 without. Clinical phase I data to the safety of AFFITOPE® AD01, AD02 (and AD03 – as available), spanning a time period of 20⫹ months (AD01/AD02), support the safety concept inherent