Scott Small Wes Ashford Hank Greely Sam Gandy Russell Katz

On 26 February 2009, we held a Webinar/Live Discussion with a slide presentation by Scott Small and subsequent panel discussion with legal ethicist Hank Greely at Stanford University, FDA representative Russell Katz, and clinician-researchers John (Wes) Ashford, also at Stanford, and Sam Gandy, Mount Sinai School of Medicine, New York.

This live discussion began with a Webinar featuring a slide talk with audio provided via a telephone line. Following the talk, the audience moved to a chatroom for Q&A and discussion. View/Listen to the Webinar Click on this image to launch the recording. Editor's note: On 3 February 2009, NPR broadcast Mind-Enhancers for All, a show based in part on the same Nature Commentary that started this Webinar discussion about drugs for cognitive aging. One of the dozens of comments noted, "In the future I will be thankful for the possibility to stay sharp when my body and mind would otherwise deteriorate." Many comments were critical of the use of drugs by healthy people.

View Transcript of Live Discussion — Posted 5 March 2009

Background Text
By Esther Landhuis and Gabrielle Strobel

Last December, a high-powered group of legal, ethical, medical, and cognitive neuroscience scholars raised eyebrows when they argued, in a Nature commentary that the use of cognition-enhancing drugs by healthy people should be considered socially acceptable. First author Henry (Hank) Greely of Stanford University, a leading voice on the legal and ethical implications of innovations in biomedicine, and colleagues furthermore outlined policy suggestions for their safe and effective development as cognitive enhancers. The opinion piece focused on the growing off-label use—primarily though not only among students and academics—of stimulants prescribed for attention deficit hyperactivity disorder, but it also mentioned the possibility of a modest memory boost for healthy people from the acetylcholinesterase inhibitors that are widely prescribed for Alzheimer disease. Occasional reports of AD drug use by cognitively normal people have cropped up anecdotally, and a small literature exists on this issue (e.g., Yesavage et al., 2002; Grön et al., 2005; Chuah and Chee, 2008; FitzGerald et al., 2008). The Alzforum set out to get a sense for how commonly AD drugs might be used as enhancers of choice. According to some noted AD clinicians, use of AD medications among the healthy appears rare and limited to short-term benefit.

But out of this conversation emerged a related topic that represents a more relevant and equally challenging discussion for Alzforum readers: that is, should the field develop drugs for the cognitive decline that accompanies “normal” aging? And if indeed this is considered legitimate in a changing society—where people live longer, with high expectations for continued mental acuity and productivity into old age—then how would researchers go about finding such drugs? This, in a sense, is the opposite question: not to give drugs originally developed to treat Alzheimer’s as cognitive enhancers to normal people, but rather to develop drugs specifically to prevent “normal” memory loss as people age.

Decades ago, investigators believed age-related memory loss simply represented early-stage AD. By now, however, converging evidence from studies in people, non-human primates, and rodents has pinpointed brain regions with a differential vulnerability to AD and to non-pathological aging. For instance, within the hippocampus early AD targets the entorhinal cortex, causing neuronal loss there (Scheff et al., 2005; Killiany et al., 2002), whereas normal aging tends to hit a neighboring subregion, the dentate gyrus, much harder than the entorhinal cortex (Chawla and Barnes, 2007). In particular, in December 2008 a team led by Scott Small at Columbia University, New York, identified age-related elevation in blood glucose concentration as a potential culprit underlying age-related memory loss that is distinct from AD (Wu et al., 2008). The work—which combined magnetic resonance imaging (MRI) of 240 non-demented elders with follow-up functional MRI studies in monkeys and mice—suggests that maintaining normal glucose levels could help preserve cognitive function in healthy elders. Small’s lab has begun to identify compounds that differentially improve the function of the dentate gyrus and therefore might stem normal age-related cognitive decline.

Suggested questions for discussion:

• Should investigators develop cognition-enhancing drugs to stem a process that occurs “normally” (i.e., aging)? Is this treatment or enhancement? What exactly does “normal” mean in this context?
• On what grounds might such drugs be considered ethical? How would this differ from previous attempts at cognitive enhancement, such as with ampakines and similar drugs?
• What would be the molecular targets of drugs for normal aging?
• Would such drugs benefit people with AD, vascular dementia, or ischemic brain damage, as well, even though they are not the intended target group?
• What is the regulatory stance toward drugs treating cognitive aging?

References:
Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M, Campbell P, Farah MJ. Towards responsible use of cognitive-enhancing drugs by the healthy. Nature. 2008 Dec 11;456(7223):702-5. Abstract

Wu W, Brickman AM, Luchsinger J, Ferrazzano P, Pichiule P, Yoshita M, Brown T, DeCarli C, Barnes CA, Mayeux R, Vannucci SJ, Small SA. The brain in the age of old: the hippocampal formation is targeted differentially by diseases of late life. Ann Neurol. 2008 Dec;64(6):698-706. Abstract

	Comments on Live Discussion
	Comment by:  John (Wes) Ashford
	Submitted 26 February 2009  |  Permalink	Posted 26 February 2009
	1. I believe there is no evidence that any Alzheimer medication helps individuals without dementia. The MCI trials have been negative or showed a preponderance of adverse effects. Under normal and early AD circumstances, neurotransmitters in the brain are carefully balanced to cope with the complexities of the world. 2. Cholinesterase inhibitor medications appear to be severely addictive. Patients go into steep declines when they discontinue these drugs; that is likely due to a reactive super-production in the brain of cholinesterase molecules. 3. Memantine has only been shown to help moderately to severely demented patients, and it can be deleterious in mildly demented patients. 4. There is no long-term objective evidence that the currently available, legal, and widely used cognition-altering drugs—nicotine, caffeine, and ethanol—actually benefit anybody. 5. Before we advocate for the addition of any substance to be added for routine use by any individual, society, or species, there should be extensive evidence of exactly whom it helps, how much it helps, and...  Read more 1. I believe there is no evidence that any Alzheimer medication helps individuals without dementia. The MCI trials have been negative or showed a preponderance of adverse effects. Under normal and early AD circumstances, neurotransmitters in the brain are carefully balanced to cope with the complexities of the world. 2. Cholinesterase inhibitor medications appear to be severely addictive. Patients go into steep declines when they discontinue these drugs; that is likely due to a reactive super-production in the brain of cholinesterase molecules. 3. Memantine has only been shown to help moderately to severely demented patients, and it can be deleterious in mildly demented patients. 4. There is no long-term objective evidence that the currently available, legal, and widely used cognition-altering drugs—nicotine, caffeine, and ethanol—actually benefit anybody. 5. Before we advocate for the addition of any substance to be added for routine use by any individual, society, or species, there should be extensive evidence of exactly whom it helps, how much it helps, and what the costs and adverse effects are, particularly over very long periods of time. 6. The important direction for drug development is to determine what treatment can benefit a person's life, particularly by stopping a process that has been clearly recognized as deleterious and pathological. In this case, we still need to define the pathological process. 7. To me, treating aging per se does not make sense since aging is just the accumulation of responses to stress over the lifetime of the individual as redundant systems lose their capacity to deal with normal world events. It is the pathological process that occurs more specifically in a single individual or group of individuals that is of interest. Then, the basis of that process can be understood—either genetic or environmental, and steps may be considered to prevent that process from developing. 8. Genetic factors that lead to specific deficits should be understood, and therapies should be developed to mitigate those factors. In my view, a great deal of benefit could be had by further understanding the relationship between the apolipoprotein E subtypes and their relationship to Alzheimer pathology, particularly with respect to how dietary adjustments could delay the development of Alzheimer pathology. View all comments by John (Wes) Ashford
	Comment by:  John (Wes) Ashford
	Submitted 13 March 2009  |  Permalink	Posted 13 March 2009
	I have two comments that I still feel need to be clarified with respect to Dr. Small's presentation. 1. The difference between normal and pathological aging is artificial. As long as you are alive, you are surviving. When you are dead, it doesn't matter what you call it. Four different aspects of aging are studied: Developmental mortality, in which risk declines with age (childhood). The Makeham component—a constant mortality factor that follows principles of decay, including radioactive decay (e.g., getting hit by an asteroid). Gompertz law—exponential increase of mortality with age. Healthy survivor effect (or late-life mortality deceleration) in which mortality seems to level off at extreme old age. All problems, including mortality, are both pathological and normal aging. Mortality is the most serious problem a living organism can face, natural though it is. Alzheimer disease is actually more closely related to aging than to mortality itself. For more on the Gompertz-Makeham law, see this   Read more I have two comments that I still feel need to be clarified with respect to Dr. Small's presentation. 1. The difference between normal and pathological aging is artificial. As long as you are alive, you are surviving. When you are dead, it doesn't matter what you call it. Four different aspects of aging are studied: Developmental mortality, in which risk declines with age (childhood). The Makeham component—a constant mortality factor that follows principles of decay, including radioactive decay (e.g., getting hit by an asteroid). Gompertz law—exponential increase of mortality with age. Healthy survivor effect (or late-life mortality deceleration) in which mortality seems to level off at extreme old age. All problems, including mortality, are both pathological and normal aging. Mortality is the most serious problem a living organism can face, natural though it is. Alzheimer disease is actually more closely related to aging than to mortality itself. For more on the Gompertz-Makeham law, see this article. For more on how aging theory relates to understanding Alzheimer disease, and how this relationship could aid the development of new AD treatments, see Ashford et al., 2004 [.pdf]. 2. As problems develop with age, they need to be addressed in the most cost-efficient means possible. That is what Dr. Katz pointed out is the critical issue in the FDA's decision-making process. But the more data and the longest view of the data possible are important. View all comments by John (Wes) Ashford
	Comment by:  John Resort
	Submitted 14 April 2009  |  Permalink	Posted 21 April 2009
	Memory loss will be a bad disease to live with as we will forget how were living. To cure this, of course some drugs should be develop. View all comments by John Resort

	Submit a Comment on this Live Discussion
	Cast your vote and/or make a comment on this live discussion.  If you already are a member, please login. Not sure if you are a member? Search our member database. *First Name   *Last Name   Country or Territory: USA Canada Afghanistan Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burma Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos Islands Colombia Comoros Congo Cook Islands Corte d'lvoire (formerly Ivory Coast) Costa Rica Croatia Cuba Cyprus Czech Republic Denmark Djibouti Dominica Dominican Republic East Timor Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Gambia Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guinea Guinea-Bissau Guyana Haiti Heard and McDonald Islands Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Ivory Coast (now known as Corte d'lvoire) Jamaica Japan Jordan Kazakhstan Kenya Kiribati Korea, North Korea, South Kuwait Kyrgyzstan Laos Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macau Macedonia ( Former Yugoslav Republic of) Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Micronesia ( Federated States of) Moldova Monaco Mongolia Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island Northern Mariana Islands Norway Oman Pakistan Palau Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Island Poland Portugal Puerto Rico Qatar Reunion Romania Russia Rwanda S. Georgia and S. Sandwich Isls. Saint Kitts & Nevis Saint Lucia Saint Vincent and The Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Seychelles Sierra Leone Singapore Slovakia Slovenia Somalia South Africa Spain Sri Lanka St. Helena St. Pierre and Miquelon Sudan Suriname Svalbard and Jan Mayen Islands Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu U.S. Minor Outlying Islands U.S.A. Uganda Ukraine United Arab Emirates United Kingdom Uruguay Uzbekistan Vanuatu Vatican City Venezuela Vietnam Virgin Islands Wallis and Futuna Islands Western Sahara Yemen Yugoslavia (Former) Zaire Zambia Zimbabwe *Login Email Address   *Password    Minimum of 8 characters *Confirm Password   Stay signed in?   Comment: (If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.) References: *Enter the verification code you see in the picture below: This helps Alzforum prevent automated registrations. Terms and Conditions of Use: Printable Version By clicking on the 'I accept' below, you are agreeing to the Terms and Conditions of Use above.