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COMMENTARY |
First of all, we would like to thank all of the commentators for their thoughtful reflections on our hypothesis. The diverse knowledge that they brought to their careful reviews has provided important additional information, e.g., the valuable epidemiologic data cited by Vischer and colleagues (1), Bank's emphasis on the role of the blood–brain barrier (2), and Vellas and Sinclair's discussion of human as well as animal studies on body mass index and risk for dementia (3).
By expressing their divergent views, the commentators have put into perspective the place of our hypothesis within the current knowledge base. For example, Lyketsos and Lee (4) as well as Newcomer (5) argue in favor of vascular disease as the major link between depression and dementia. Indeed, the frequent coexistence of neuropathologic changes characteristic of vascular disease and Alzheimer's disease (AD) is well established. We do not agree with Newcomer, however, that vascular disease rather than AD "is the predicted outcome for depressed individuals with insulin resistance that is most clearly supported by existing research." We believe that existing data are inadequate to support a dichotomous choice.
Indeed, the commentators were unanimous in pointing to the need for additional information at all levels of scientific inquiry. This state of affairs led Lyketsos and Lee (4) to conclude: "While a link between insulin resistance and AD is an interesting proposition, it remains in its nascent phases." We agree. We also agree with Vischer and colleagues (1) that it remains to be demonstrated whether "therapeutic interventions targeted at long-term correction of insulin resistance can improve functional status in AD patients." In addition, we believe that it is also important to establish whether such interventions can postpone or prevent the manifestations of AD, regardless of whether the association between insulin resistance (IR) and AD turns out to be secondary or causal. Indeed, it is our view that the observed association between IR and AD represents the outcome of several rather than a single pathogenic process.
There are so many more ideas, suggestions, and comments worthy of response that it is not possible for us to address them all. We will mention only one more, a recommendation for therapeutic intervention by Vellas and Sinclair (3). They suggest that appropriately controlled clinical trials of dietary restriction, not necessarily limited to patients with affective disorder, be initiated to test for potential reduction in neuronal damage. In our opinion, even though there still is so much to be learned about the role of IR as a risk factor for AD, and the complex relation between IR, affective disorders, and AD, research at the clinical level is needed as well as exploration of neuropathologic, genetic, physiologic, and other basic science issues. We hope that researchers will find our hypothesis useful in guiding some of their explorations, and thereby, serve the purpose of our hypothesis, i.e., "Draw out and test its logical or empirical consequences" (6).
Acknowledgments
Address correspondence to Natalie Rasgon, MD, PhD, Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, 401 Quarry Rd., Rm. 2360, Palo Alto, CA 94305-5723. E-mail: nrasgon{at}stanford.edu
References
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