- Email: [email protected]
34 Hormone therapy in dementia prevention: The women's health initiative memory Study
FIFTH INTERNATIONAL
CONFERENCE
ON ALZHEIMER'S
of 70 or 75. Other risk factors, such as positive family history or Apolipoprotein E status could be use to enrich the population although such cndc,hment reduces the general ability ofthc trial. With an incidence of 11.5% per annum in an over age 75 population results in a 5-7.5% cumulative incidence of AD over 5 years. Sample sizes of approximately 2,000 subjects per group would result in 100-150 cases per group. Ifa drug reduced the incidents of AD by 50%, 50-75 cases would exist in the treated group. Such findings would be both statisticallysignificant and sufficiently robust to be clinically meaningful. Thus, allowing for deaths and losses, a total sample size of almost 5,000 individuals would be needed to carry out such a trial. The primary endpoint would be the development of clinically diagnosable AD, an endpoint requiring sophistication and judgment. The cost for such a trial would be in excess of $20 million and the duration of follow up would be 5 years. Altemate less costly alternatives would be the development of an "add-on" trial where the end point of dementia is added to an ongoing trial or the use of an "at risk" protocol which requires fewer subjects.
32 Mild Cognitive Impairment as a Focus for Therapeutic Intervention R.C. Petersen Department of Neurology, Mayo Clinic, Rochester, MN 55905 Cognition can be characterized along a continuum from normal function through a phase of mild impairment ultimately to dementia. Along this continuum is a transitional phase known as mild cognitive impairment through which most patients will pass if they are destined to become demented. The stage of mild cognitive impairment can be characterized as involving those individuals who have a memory difficulty but are otherwise functioning well. Their general cognitive function and activities of dally living are normal, but their memory performance is abnormal for age. These patients do not reach criteria for dementia and can be characterized on the Clinical Dementia Rating scale as a 0.5. Longitudinal studies of these patients indicate that these subjects progress to dementia at a rate of approximately 15 percent per year whereas suitable control populations convert to dementia at a rate of 1-2 percent per year. Predictors of progression to dementia include the apolipoprotein E status of the patients and certain features of their memory function at the time of initial diagnosis. These patients constitute a group of individuals that can be characterized clinically, and their rate of progression to dementia is known. As such, they represent a target for therapeutic intervention in an attempt to retard delay the progression.
DISEASE
$9
potentially important preventive measures are likely to have effects that will be difficult to evaluate clearly in observational studies alone because of confounding and because the effects of each will be small to moderate in magnitude. Properly designed trials of adequate size will very likely be required for definitive information.
34 Hormone Therapy in Dementia Prevention: The Women's Health Initiative Memory Study S. Shumaker and S. Rapp The Bowman Gray School of Medicine, Department of Public Health Sciences and Psychiatry, Wake Forest University, Medical Center Boulevard, Winston-Salem, NC 27157-1063, USA. The Women's Health Initiative (WHI) represents one of the largest studies ever conducted on women's health. WHI is comprised of a group of studies imbedded into a large cohort of over 120,000 postmenopansal women, selected from over 40 clinical centers in the United States, who are between the ages of 50 and 79 at study baseline. In WHI there are three randomized clinical trials (lowfat diet vs. usual diet; hormone therapy vs. placebo; and, calcium/vitaminD vs. placebo) and an observational study. Women are currently being enrolled into the studies and they will be followed from nine to twelve years. Primary outcomes include: cardiovascular diseases, breast and colorectal cancers, and osteoporosis. The WHI-Memory Study (WHIMS) is an ancillary study to the HRT clinical trial of WHI. Women 65 years of age and older who are participating in the HRT are eligible for recruitment into WHIMS at the time o f their randomization into HRT. It is hypothesized that the development and progression of dementia will be delayed and slowed, respectively, in women who are on active HKT (EKT and PEKT) as opposed to placebo. Women will be tested at baseline and annually thereafter for up to six years in order to identify dementia cases. Classification ofdementin will be based on laboratory data (blood work and CT) obtained from all probable cases. It is anticipated that approximately 8,000 women will participate in WHIMS. The study is designed to provide greater than 80% statistical power to detect a 40% treatment effect on the incidence ofall-canse dementia. WHIMS represents an ambitious effort to experimentally assess the efficacy of HKT in preventing and slowing the progression of dementia in post-menopausal women. Furthermore, by taking advantage of an ongoing study with an ageappropriate study cohort, trained and experienced personnel, and a strong system of quality control, WHIMS will be conducted in a relatively costeffective manner.
33 Epidemiology of Aizheimer's Disease and Clues to Treatment D. A. Evans* Rush Alzheimer's Disease Center, Rush University and Rush-PresbyterianSt. Luke's Medical Center, Chicago, Illinois, U.S.A. Alzheimer's disease is a common condition that has a devastating impact on the lives of persons with the illness and their families. Because its occurrence is strongly related to age, the number of persons with the illness will continue to grow with the aging of the populations of developed countries. Prevention of Alzheimer's disease is, therefore, an urgent priority. Identification of potentially reversible risk factors is a necessary step in formulating preventive strategies. Unfortunately, knowledge of risk factors for Alzheimer's disease is at an early stage and is limited by many considerations, including the methodology features of current epidemiologieal studies and limited understanding of the basic mechanisms of the disease. Possible risk factors with potential for modification include estrogen hormone replacement therapy, intake of antioxidant nutritional supplements, intake of non-steroidal antiinflammatory drugs and use of one's cognitive abilities through life. For other common chronic diseases, credible epidemiological evidence regarding risk factors has come from longitudinal population studies of incident disease that have adequate size and strong design features, and definitive evidence for preventive measures has come from large-scale randomized trials of primary prevention. Currently available evidence concerning risk factors for Alzheimer's disease, however, is mostly from cross-sectional studies, often of clinical samples. The need for large observational studies of incident disease is clear and pressing. How quickly to progress to large trials of primary prevention is more difficult to assess, but two considerations argue for undertaking such trials in the near future. The first is the seriousness of the problem: a common, severe illness with only limited options for treatment. The second is that
ROUNDTABLE D: NICOTINIC AGONISTS AND ALZHEIMER'S DISEASE 35 Nicotinic receptors (nAChR) in the brain : g e n e e x p r e s s i o n and contribution to l e a r n i n g and aging processes Jean-Pierre C h a n g e u x , A l a i n Bessis, Marina Picciotto & Michele Zoli, N e u r o b i o l o g i e Mol~culaire, Institut Pasteur, Paris, France Distributions of n A C h R s u b u n i t s m R N A s is f o l l o w e d b y in situ h y b r i d i z a t i o n m e t h o d in the c o u r s e of e m b r y o n i c a n d p o s t n a t a l d e v e l o p m e n t in the rat. Early e x p r e s s i o n of c~3, a4, 82, ~4 m R N A s coincides w i t h n e u r o n a l differentiation ; s u b s e q u e n t l y , in the cerebral cortex, a3 m R N A is repressed w h i l e ct4 m R N A is induced. 1) Analysis of the 82 s u b u n i t p r o m o t e r by t r a n s f e c t i o n of cell c u l t u r e s or in transgenic mice, reveal two n e g a t i v e e l e m e n t s ( i n c l u d i n g a NRSE/RE sequence) a n d one positive e l e m e n t (E Box) ; moreover, m u t a t i o n of the N R S E / R E sequence causes in transgenic mice a d r a m a t i c change in e x p r e s s i o n p a t t e r n . N i c o t i n e affects m a n y a s p e c t s of b e h a v i o u r i n c l u d i n g a d d i c t i o n , l e a r n i n g a n d m e m o r y via its i n t e r a c t i o n w i t h n e u r o n a l n i c o t i n i c a c e t y l c h o l i n e r e c e p t o r s ( n A C h R ) w h i c h are p e n t a m e r i c proteins containing at least one type of a - s u b u n i t a n d one type of ~-subunit. The contribution of a particular n A C h R s u b u n i t to these b e h a v i o u r s w a s e x a m i n e d u s i n g gene targeting to m u t a t e the 82
CONFERENCE
ON ALZHEIMER'S
of 70 or 75. Other risk factors, such as positive family history or Apolipoprotein E status could be use to enrich the population although such cndc,hment reduces the general ability ofthc trial. With an incidence of 11.5% per annum in an over age 75 population results in a 5-7.5% cumulative incidence of AD over 5 years. Sample sizes of approximately 2,000 subjects per group would result in 100-150 cases per group. Ifa drug reduced the incidents of AD by 50%, 50-75 cases would exist in the treated group. Such findings would be both statisticallysignificant and sufficiently robust to be clinically meaningful. Thus, allowing for deaths and losses, a total sample size of almost 5,000 individuals would be needed to carry out such a trial. The primary endpoint would be the development of clinically diagnosable AD, an endpoint requiring sophistication and judgment. The cost for such a trial would be in excess of $20 million and the duration of follow up would be 5 years. Altemate less costly alternatives would be the development of an "add-on" trial where the end point of dementia is added to an ongoing trial or the use of an "at risk" protocol which requires fewer subjects.
32 Mild Cognitive Impairment as a Focus for Therapeutic Intervention R.C. Petersen Department of Neurology, Mayo Clinic, Rochester, MN 55905 Cognition can be characterized along a continuum from normal function through a phase of mild impairment ultimately to dementia. Along this continuum is a transitional phase known as mild cognitive impairment through which most patients will pass if they are destined to become demented. The stage of mild cognitive impairment can be characterized as involving those individuals who have a memory difficulty but are otherwise functioning well. Their general cognitive function and activities of dally living are normal, but their memory performance is abnormal for age. These patients do not reach criteria for dementia and can be characterized on the Clinical Dementia Rating scale as a 0.5. Longitudinal studies of these patients indicate that these subjects progress to dementia at a rate of approximately 15 percent per year whereas suitable control populations convert to dementia at a rate of 1-2 percent per year. Predictors of progression to dementia include the apolipoprotein E status of the patients and certain features of their memory function at the time of initial diagnosis. These patients constitute a group of individuals that can be characterized clinically, and their rate of progression to dementia is known. As such, they represent a target for therapeutic intervention in an attempt to retard delay the progression.
DISEASE
$9
potentially important preventive measures are likely to have effects that will be difficult to evaluate clearly in observational studies alone because of confounding and because the effects of each will be small to moderate in magnitude. Properly designed trials of adequate size will very likely be required for definitive information.
34 Hormone Therapy in Dementia Prevention: The Women's Health Initiative Memory Study S. Shumaker and S. Rapp The Bowman Gray School of Medicine, Department of Public Health Sciences and Psychiatry, Wake Forest University, Medical Center Boulevard, Winston-Salem, NC 27157-1063, USA. The Women's Health Initiative (WHI) represents one of the largest studies ever conducted on women's health. WHI is comprised of a group of studies imbedded into a large cohort of over 120,000 postmenopansal women, selected from over 40 clinical centers in the United States, who are between the ages of 50 and 79 at study baseline. In WHI there are three randomized clinical trials (lowfat diet vs. usual diet; hormone therapy vs. placebo; and, calcium/vitaminD vs. placebo) and an observational study. Women are currently being enrolled into the studies and they will be followed from nine to twelve years. Primary outcomes include: cardiovascular diseases, breast and colorectal cancers, and osteoporosis. The WHI-Memory Study (WHIMS) is an ancillary study to the HRT clinical trial of WHI. Women 65 years of age and older who are participating in the HRT are eligible for recruitment into WHIMS at the time o f their randomization into HRT. It is hypothesized that the development and progression of dementia will be delayed and slowed, respectively, in women who are on active HKT (EKT and PEKT) as opposed to placebo. Women will be tested at baseline and annually thereafter for up to six years in order to identify dementia cases. Classification ofdementin will be based on laboratory data (blood work and CT) obtained from all probable cases. It is anticipated that approximately 8,000 women will participate in WHIMS. The study is designed to provide greater than 80% statistical power to detect a 40% treatment effect on the incidence ofall-canse dementia. WHIMS represents an ambitious effort to experimentally assess the efficacy of HKT in preventing and slowing the progression of dementia in post-menopausal women. Furthermore, by taking advantage of an ongoing study with an ageappropriate study cohort, trained and experienced personnel, and a strong system of quality control, WHIMS will be conducted in a relatively costeffective manner.
33 Epidemiology of Aizheimer's Disease and Clues to Treatment D. A. Evans* Rush Alzheimer's Disease Center, Rush University and Rush-PresbyterianSt. Luke's Medical Center, Chicago, Illinois, U.S.A. Alzheimer's disease is a common condition that has a devastating impact on the lives of persons with the illness and their families. Because its occurrence is strongly related to age, the number of persons with the illness will continue to grow with the aging of the populations of developed countries. Prevention of Alzheimer's disease is, therefore, an urgent priority. Identification of potentially reversible risk factors is a necessary step in formulating preventive strategies. Unfortunately, knowledge of risk factors for Alzheimer's disease is at an early stage and is limited by many considerations, including the methodology features of current epidemiologieal studies and limited understanding of the basic mechanisms of the disease. Possible risk factors with potential for modification include estrogen hormone replacement therapy, intake of antioxidant nutritional supplements, intake of non-steroidal antiinflammatory drugs and use of one's cognitive abilities through life. For other common chronic diseases, credible epidemiological evidence regarding risk factors has come from longitudinal population studies of incident disease that have adequate size and strong design features, and definitive evidence for preventive measures has come from large-scale randomized trials of primary prevention. Currently available evidence concerning risk factors for Alzheimer's disease, however, is mostly from cross-sectional studies, often of clinical samples. The need for large observational studies of incident disease is clear and pressing. How quickly to progress to large trials of primary prevention is more difficult to assess, but two considerations argue for undertaking such trials in the near future. The first is the seriousness of the problem: a common, severe illness with only limited options for treatment. The second is that
ROUNDTABLE D: NICOTINIC AGONISTS AND ALZHEIMER'S DISEASE 35 Nicotinic receptors (nAChR) in the brain : g e n e e x p r e s s i o n and contribution to l e a r n i n g and aging processes Jean-Pierre C h a n g e u x , A l a i n Bessis, Marina Picciotto & Michele Zoli, N e u r o b i o l o g i e Mol~culaire, Institut Pasteur, Paris, France Distributions of n A C h R s u b u n i t s m R N A s is f o l l o w e d b y in situ h y b r i d i z a t i o n m e t h o d in the c o u r s e of e m b r y o n i c a n d p o s t n a t a l d e v e l o p m e n t in the rat. Early e x p r e s s i o n of c~3, a4, 82, ~4 m R N A s coincides w i t h n e u r o n a l differentiation ; s u b s e q u e n t l y , in the cerebral cortex, a3 m R N A is repressed w h i l e ct4 m R N A is induced. 1) Analysis of the 82 s u b u n i t p r o m o t e r by t r a n s f e c t i o n of cell c u l t u r e s or in transgenic mice, reveal two n e g a t i v e e l e m e n t s ( i n c l u d i n g a NRSE/RE sequence) a n d one positive e l e m e n t (E Box) ; moreover, m u t a t i o n of the N R S E / R E sequence causes in transgenic mice a d r a m a t i c change in e x p r e s s i o n p a t t e r n . N i c o t i n e affects m a n y a s p e c t s of b e h a v i o u r i n c l u d i n g a d d i c t i o n , l e a r n i n g a n d m e m o r y via its i n t e r a c t i o n w i t h n e u r o n a l n i c o t i n i c a c e t y l c h o l i n e r e c e p t o r s ( n A C h R ) w h i c h are p e n t a m e r i c proteins containing at least one type of a - s u b u n i t a n d one type of ~-subunit. The contribution of a particular n A C h R s u b u n i t to these b e h a v i o u r s w a s e x a m i n e d u s i n g gene targeting to m u t a t e the 82