- Email: [email protected]
71 Are we ready to perform clinical trials in early AD patients? which patients, which outcomes?
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
to AFFITOPE® AD vaccines. The recently completed analysis of secondary clinical endpoints of AD02-based treatment – regarding parameters such as the cognitive/functional performance of the patients (as assessed among others by MMSE, ADAScog, ADL), body weight development and vaccine induced immune responses over a time period of 20⫹ months – provides evidence for a disease modifying activity of AFFITOPE AD02®. This was particularly evident in patients who entered the phase I study at an early stage of their disease. The above results led AFFiRiS to initiate a multicenter phase II study aimed at evaluating the clinical activity AFFITOPE AD02®. The study design already takes into account the indicatory results of the phase I study and will include a several hundred patients with early AD.
able, often not linear in its progression, many patients don’t decline over a given 1 to 3 year observed period. Measuring reliable change with any outcome is formidable when there is little change. Measures that seem to be more precise and change the most are fraught with expectation bias. The accuracy of early AD diagnosis will improve. We need however, to develop outcomes specific to individual patients and efficient trials methods that take into account the varieties of individual responses and that only a subset of patients will likely benefit from any particular drug. Onesize-fits-all-outcomes will not be efficient. The model of action of a drug being developed should determine inclusion criteria, trials durations, and outcomes.
72 71
ARE WE READY TO PERFORM CLINICAL TRIALS IN EARLY AD PATIENTS? WHICH PATIENTS, WHICH OUTCOMES?
Lon S. Schneider, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Contact e-mail: [email protected] Trials in early AD have been performed for 2 decades; we are beyond ready. An accurate title for the session could be, “Are We Ready to Explicitly Recognize Early AD and Do Better Trials?” The early cognitive impairment phase of AD was recognized since the late 1980s but called different names. Trials inclusion criteria from the late 1980s onward implicitly provided for early AD patients by allowing MMSE scores 24 to 27 and clinicians’ judgments of impaired ADLs. Similarly, MCI studies included patients with early AD. MCI trials, from 1999 onward, and ADNI used Mayo Clinic criteria, essentially MCI due to AD, and the same as the proposed AA/NIH research criteria. The more memoryimpaired patients in these cohorts — about two-thirds — are indistinguishable from and could have been diagnosed as AD. As a group, they were very likely to progress over a short time; and far more likely to have putative AD biomarkers or be ApoE4 carriers. Conversely, the less impaired were not likely to progress or to have positive biomarkers. Distinctions between MCI due to AD, prodromal AD, early AD, mild AD, and similar terms may be without practical differences or too subtle for reliable use, with judgments about the extent of impaired function mainly determining diagnosis. In the context of MCI or early AD diagnoses, current biomarkers, claimed to be useful in identifying AD early in its course, may ironically identify more advanced AD. As AD is very slowly progressive on average, highly vari-
S31
INFLUENCE OF MID-LIFE RISK FACTORS ON LATE LIFE COGNITIVE AND WHITE MATTER CHANGES: HOW SHOULD WE TIME PREVENTIVE INTERVENTIONS?
Ingmar Skoog, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unite, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden. Contact e-mail: [email protected] Late-life cognitive disorders are common. The most common causes are Alzheimer’s disease and vascular brain lesions, such as cerebral white matter lesions (WMLs). During recent years evidence has accumulated that mid-life factors may influence the risk for both Alzheimer’s disease and WMLs. These include factors previously known to affect vascular disease, such as hypertension, diabetes mellitus and hypercholesterolemia. Late-life cognitive disorders have also been related to other life-style factors in mid-life, such as psychological stress, physical activity and lung function, engagement in different hobbies, wine consumption, diet and intellectual activity. Most of these have also been related to WMLs in late life, although hypertension is the main risk factor for these lesions. In the PROGRESS trial, which included individuals with a history of stroke, treatment with antihypertensives reduced the occurrence of new white matter lesions significantly. Vascular risk factors, such as hypertension and hypercholesterolemia, already have indications for treatment due to the proven effect in randomized controlled trials on risk for cardiovascular and cerebrovascular end-points and mortality. The main problem here is to detect individuals with these risk factors. It is not likely that it will ever be practically possible to conduct RCTs in middle aged populations to test whether preventive strategies will decrease the risk of dementia in old age (maybe 30 years later). Detection of vascular risk factors is however most likely important to prevent Alzheimer’s disease and WMLs in late life. Advice regarding a healthy life
to AFFITOPE® AD vaccines. The recently completed analysis of secondary clinical endpoints of AD02-based treatment – regarding parameters such as the cognitive/functional performance of the patients (as assessed among others by MMSE, ADAScog, ADL), body weight development and vaccine induced immune responses over a time period of 20⫹ months – provides evidence for a disease modifying activity of AFFITOPE AD02®. This was particularly evident in patients who entered the phase I study at an early stage of their disease. The above results led AFFiRiS to initiate a multicenter phase II study aimed at evaluating the clinical activity AFFITOPE AD02®. The study design already takes into account the indicatory results of the phase I study and will include a several hundred patients with early AD.
able, often not linear in its progression, many patients don’t decline over a given 1 to 3 year observed period. Measuring reliable change with any outcome is formidable when there is little change. Measures that seem to be more precise and change the most are fraught with expectation bias. The accuracy of early AD diagnosis will improve. We need however, to develop outcomes specific to individual patients and efficient trials methods that take into account the varieties of individual responses and that only a subset of patients will likely benefit from any particular drug. Onesize-fits-all-outcomes will not be efficient. The model of action of a drug being developed should determine inclusion criteria, trials durations, and outcomes.
72 71
ARE WE READY TO PERFORM CLINICAL TRIALS IN EARLY AD PATIENTS? WHICH PATIENTS, WHICH OUTCOMES?
Lon S. Schneider, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Contact e-mail: [email protected] Trials in early AD have been performed for 2 decades; we are beyond ready. An accurate title for the session could be, “Are We Ready to Explicitly Recognize Early AD and Do Better Trials?” The early cognitive impairment phase of AD was recognized since the late 1980s but called different names. Trials inclusion criteria from the late 1980s onward implicitly provided for early AD patients by allowing MMSE scores 24 to 27 and clinicians’ judgments of impaired ADLs. Similarly, MCI studies included patients with early AD. MCI trials, from 1999 onward, and ADNI used Mayo Clinic criteria, essentially MCI due to AD, and the same as the proposed AA/NIH research criteria. The more memoryimpaired patients in these cohorts — about two-thirds — are indistinguishable from and could have been diagnosed as AD. As a group, they were very likely to progress over a short time; and far more likely to have putative AD biomarkers or be ApoE4 carriers. Conversely, the less impaired were not likely to progress or to have positive biomarkers. Distinctions between MCI due to AD, prodromal AD, early AD, mild AD, and similar terms may be without practical differences or too subtle for reliable use, with judgments about the extent of impaired function mainly determining diagnosis. In the context of MCI or early AD diagnoses, current biomarkers, claimed to be useful in identifying AD early in its course, may ironically identify more advanced AD. As AD is very slowly progressive on average, highly vari-
S31
INFLUENCE OF MID-LIFE RISK FACTORS ON LATE LIFE COGNITIVE AND WHITE MATTER CHANGES: HOW SHOULD WE TIME PREVENTIVE INTERVENTIONS?
Ingmar Skoog, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unite, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden. Contact e-mail: [email protected] Late-life cognitive disorders are common. The most common causes are Alzheimer’s disease and vascular brain lesions, such as cerebral white matter lesions (WMLs). During recent years evidence has accumulated that mid-life factors may influence the risk for both Alzheimer’s disease and WMLs. These include factors previously known to affect vascular disease, such as hypertension, diabetes mellitus and hypercholesterolemia. Late-life cognitive disorders have also been related to other life-style factors in mid-life, such as psychological stress, physical activity and lung function, engagement in different hobbies, wine consumption, diet and intellectual activity. Most of these have also been related to WMLs in late life, although hypertension is the main risk factor for these lesions. In the PROGRESS trial, which included individuals with a history of stroke, treatment with antihypertensives reduced the occurrence of new white matter lesions significantly. Vascular risk factors, such as hypertension and hypercholesterolemia, already have indications for treatment due to the proven effect in randomized controlled trials on risk for cardiovascular and cerebrovascular end-points and mortality. The main problem here is to detect individuals with these risk factors. It is not likely that it will ever be practically possible to conduct RCTs in middle aged populations to test whether preventive strategies will decrease the risk of dementia in old age (maybe 30 years later). Detection of vascular risk factors is however most likely important to prevent Alzheimer’s disease and WMLs in late life. Advice regarding a healthy life