Introduction

Our thanks to the Journal of Gerontology for granting permission to post the full text article.

Natalie Rasgon led this live discussion on 6 July 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Participants: Participants: Natalie Rasgon, Stanford University; Anne Fagan, Washington University, St. Louis; David Ewbank, University of Pennsylvania; Patricia Taylor, Speech Therapist; Michael Marlatt, Case Western Reserve University; Patricia Heyn, University of Colorado Health Sciences Center; Suzanne de la Monte, Brown University; Nancy Emerson Lombardo, Boston University.

June Kinoshita
Hello, everyone. Welcome! Dr. Rasgon, thank you for inspiring this discussion!

Natalie Rasgon
My pleasure.

June Kinoshita
Okay, I think we should get the discussion started. Could we all briefly describe our interest in today's topic. That will provide a frame of reference. I'm the editor of the Alzforum and am interested in ideas that might help to pull together a bigger picture of what is going on in AD.

Patricia Heyn
My father supposedly had Alzheimer disease (AD). He demonstrated many characteristics regarding his desire to communicate that were not addressed through the medical community. I have developed a great interest in facilitating communication in this population.

Anne Fagan
I'm a researcher interested in AD biomarkers and risk factors. I must admit, I'm here mostly to learn since I don't know much about the specific topic today.

Mike Marlatt
I have been doing Alzheimer disease research for a few years, especially in the topics of tau phosphorylation and oxidative stress.

June Kinoshita
Anne is co-leading a live chat two days from today on biomarkers for AD. Maybe some ideas from today's chat will spill over into that one!

David Ewbank
I'm a demographer affiliated with Penn's Alzheimer's Center. I've done some work on AD and a bit on depression. I am now starting a project on alternatives to factor analysis for defining insulin resistance syndrome (IRS). I will be using an alternative to standard meta-analysis that I developed for studying ApoE, AD, and mortality. Perhaps I can start with a question. There is a huge literature correlating ApoE genotype and anything else you can think of. However, I was struck with your comments on how ApoE might come into the IRS-depression link. I wonder if you could comment on that.

Natalie Rasgon
There is growing data on insulin effects in the CNS. In particular, Suzanne Craft's work on effects of insulin in AD patients suggests that central effects of insulin are selective for memory, e.g., insulin effects in hippocampus are of greatest interest with regard to part of AD pathophysiology.

Anne Fagan
I can jump in, too. What do you think is the biggest issue in the AD/insulin connection? Prevention, mechanisms, risk assessment, etc?

Natalie Rasgon
In addition, insulin resistance (IR) is clearly driven by various neuroendocrine permutations involved in pathophysiology of depression and that gives me an idea that IR may link depressive disorders and AD.

June Kinoshita
How would ApoE genotype enter into these links?

Natalie Rasgon
In Craft's work, ApoE modulated IR in AD patients. For example, those with ε4 allele had lower glucose disposal than those without.

Michael Marlatt
Getting back to the insulin treatment, are you expecting to increase neurotransmitter levels in the patients?

Natalie Rasgon
We had not thought of that interaction in terms of quantitative analysis, but it's plausible, I am more interested in behavioral and neuroimaging markers of the interaction.

Anne Fagan
What sort of neuroimaging markers would you like to look at?

June Kinoshita
Anne, what do you think about expanding AD biomarker studies to include markers for IR?

Anne Fagan
June, absolutely! I gave a talk a half year or so ago and was approached by someone afterwards who worked on IR and was interested in possibly doing a collaborative project. Never heard from him again, but it's certainly worth exploring. I'll have to do a bit of literature research to see what sort of analyses might be good to look at as a first pass.

June Kinoshita
Thanks for your comment, Anne. Maybe you can find a more responsive collaborator among today's discussants.

Nancy Emerson Lombardo
Hi, I am Nancy Emerson Lombardo, PhD, from Boston University School of Medicine. I have read this neat article and actually referenced it in things I've been writing. Lissy Jarvik is a friend from way back!

June Kinoshita
Welcome, Nancy!

Patricia Heyn
I once read that lesions in the hippocampus in AD caused word retrieval difficulties, while lesions lower in the hippocampus caused syntax difficulties in Parkinson's. The effects of insulin on memory are very interesting!

Natalie Rasgon
Currently, there are studies (see, for example, Benedict et al., 2004 and Reger et al., 2005), and we're starting one as well, to look at the effects of intranasal insulin on memory. My particular interest is in persons at risk, rather than those with MCI or an established disease. I hope that we'll get funding for it, because it will isolate the central effects of insulin from peripheral, which will further my hypothesis.

Suzanne de la Monte
I could not tell if you think depression is a central or peripheral insulin problem.

Natalie Rasgon
I think that without a doubt depression is a central insulin problem; because depression is a systemic illness, various peripheral events add on to the central component, e.g., weight gain, obesity, hypercortisolemia, changes in cytokines, etc.

Suzanne de la Monte
Is there a possibility that the peripheral insulin resistance that would compromise CNS microvascular circulation could cause depression/dementia?

Natalie Rasgon
Suzanne, vascular effects of insulin are not well-studied. I think we can infer some of it from imaging studies, which are waiting to be conducted.

David Ewbank
There seem to be two distinct AD-depression literatures: one on depression as a risk factor for MCI or AD, and a second on depressive symptoms in patients with AD. Is it your impression that these represent differences in pathology or merely differences in timing of appearance of symptoms?

Natalie Rasgon
Ewbank is right. I refer only to the presence of clinical depression long before any cognitive decline is evident; in fact, there is evidence, albeit not consistently replicated, that depression preceding AD for more than 10 years is a risk factor for AD (see, for example, Andersen et al., 2005).

Suzanne de la Monte
I agree about the depression and AD story—no controversy there. We see AD as a mixed bag with ~40 percent having overlapping cerebrovascular disease with moderate AD or AD and little vascular disease. We are doing postmortem studies to detect insulin resistance in AD, AD + vascular, and aging microvessels—not sure how to detect it in vivo.

Natalie Rasgon
I think that's exactly the case—that AD is, to a large extent, a vascular disease and as such is compounded with all consequences of atherosclerosis, and if you could show IR comparably represented in vascular versus AD brain, that'll be a great contribution to the field.

Suzanne de la Monte
So, how do you think insulin resistance in the brain causes depression? Is the depression you refer to different from psychotic depression in terms of basic etiology? This is a really interesting concept because it may have relevance to psychosis.

Natalie Rasgon
I do not think that IR causes depression. IR has been described in patients with major depressive disorder (MDD) before treatment, and my work suggested that women with bipolar disorder have high homeostasis model assessment (HOMA, and index of insulin sensitivity based on fasting glucose and insulin levels) ratios suggesting IR. In addition, women with primary IR syndromes have much higher rates of depression. Pathophysiologically, insulin is driving hypercortisolemia and vice versa, which may in turn further promote central IR.

June Kinoshita
Forgive me if I'm a bit foggy here. Does Dr. Rasgon hypothesize that the effect of IR on brain disorders is primarily through effects on vasculature? Does this contrast with Dr. de la Monte's concept of a brain-specific insulin-signaling pathway that is disrupted in AD?

Natalie Rasgon
No, June, I'm not suggesting a microvasculature component. I do not know of any evidence for that. I agree that it may be one of the components of connection, however.

Suzanne de la Monte
So, to help clarify, do you think the neurons and/or glia versus CNS vessels are insulin resistant in the depression that precedes AD? How about depression that does not precede AD?

Nancy Emerson Lombardo
Could Dr. Rasgon more fully reply to Suzanne's earlier question about the type of depression involved, etiologically.

Natalie Rasgon
I refer to depressive disorders, both bipolar and major depression; I do not think that psychotic depression is the main culprit, because IR has been described in non-psychotic MDD. I do not have pathology data, but neuroimaging data clearly suggest that in some patients with depression, clinical recovery is not followed by improvement in glucose utilization patterns; thus, it is possible that these patients may have an underlying IR.

David Ewbank
I worked on a study on late-onset depression, brain atrophy, and medical illness. I seem to remember that there were almost no late-onset depression patients who didn't have other medical conditions. Given the complex interactions among affective disorders (Ad), AD, and IRS, what is the best age group to be studying to understand the IR-Ad link?

Natalie Rasgon
Late-life depression has a different pathophysiology, and I think in many cases is a precursor, or a prodrome for Ad. I believe that we need to study IR in early depressives, because we know that neurodegeneration starts decades before it's manifested clinically.

June Kinoshita
What age ranges would you target for studying IR in early depressives?

Natalie Rasgon
Age 35-55.

June Kinoshita
Thanks.

David Ewbank
So would you start with depressives and look for IR rather than starting with IR and looking for (or waiting for) depression?

Natalie Rasgon
Great question! Actually, I'd do both.

Suzanne de la Monte
Agreed—early depression should be studied. Would it be helpful to do experiments in animals looking for the molecular phenotypes of depression with insulin resistance in the brain?

Natalie Rasgon
Absolutely; what animals would you use? Rats, monkeys?

Suzanne de la Monte
Probably rats—we have several models now. What do you think we should look for that would be clinically relevant? We could look with different severities and time durations as well as brain regions.

June Kinoshita
Dr. Rasgon, are you currently studying this group with behavioral tests and neuroimaging?

Nancy Emerson Lombardo
I have a couple of questions. One, what about anxiety, both in current AD patients and as a precursor? Any connection there with IR? Your article refers to affective disorders, but I wasn't clear which you were including.

Natalie Rasgon
I am not sure about anxiety; I was not including anxiety disorders in the hypothesis.

Nancy Emerson Lombardo
Question 2: I am studying the relationship between nutrition and dementia, especially AD, and I recently spoke with a Tufts University professor who is studying the link between nutrition and depression and anxiety. Turns out the recommended diet is very similar, as both seem to be related to, among other things, deficiencies in omega 3s, especially docosahexaenoic acid (DHA, see ARF related news story)/eicosapentaenoic acid (EPA, see ARF related news story) long chain omega 3s, and too few antioxidants.

Natalie Rasgon
Nancy, the antioxidant part of the link is there, as they are a ubiquitous part of cell function. I do agree that with dietary modification we may get changes in peripheral IR; I'm not sure about central IR, but this could be tested, again with brain imaging.

Suzanne de la Monte
Nancy, do the AD patients actually eat more before they are demented?

Nancy Emerson Lombardo
No, there are only a few studies contrasting diets of AD patients with age-matched controls and they tend to show AD patients with lower amounts of omega 3s, excess omega 6s (which would also cause inflammation), too much sugar (think IR), and fewer antioxidants (see, for example, Morris et al., 2003).

June Kinoshita
Are there blood biomarkers that one might look at to gain insight into the IR, Ad, and AD connection?

Natalie Rasgon
You can look at glucose disposal via several tests: glucose tolerance test (GTT), or euglycemic clamp, etc. [The euglycemic clamp measures the amount of glucose necessary to compensate for a set amount of insulin infused. If a patient is infused with insulin, the blood sugar levels fall. This can be compensated for by infusing glucose, as well. The clamp measures how much glucose must be infused to maintain blood sugar levels between 5 and 5.5 mmol/l. The rate of glucose infusion is determined by checking the blood sugar levels every 5 minutes. The rate of glucose infusion during the last 30 minutes of the test determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the patient is insulin-sensitive. Very low levels (4.0 mg/min or lower) suggest that the body is resistant to insulin action. Levels between 4.1 and 7.4 mg/min are indeterminate and might point at "impaired glucose tolerance," considered an early form of insulin resistance.]

Nancy Emerson Lombardo
Anyone interested in further discussions of link of diet with IR and depression, anxiety, and AD?

June Kinoshita
Nancy, we should think about an Alzforum discussion series to keep exploring these compelling links.

Nancy Emerson Lombardo
Thanks, June, for your suggestion. I think there are several people potentially interested and I agree with Suzanne; this could be a major possibility for prevention and treatment of current patients.

Suzanne de la Monte
I think we should really have a discussion of diet and AD/IR. This is where intervention could happen for the ordinary citizen.

Natalie Rasgon
I agree. I would like to know more about others' work in that area; nobody to my knowledge studies the anxiety/IR/Ad connection.

June Kinoshita
Okay!

Suzanne de la Monte
I could be wrong, but I always consider anxiety as the flip of depression, but very related.

Natalie Rasgon
Not really; anxiety is very comorbid with MDD but has distinct pathophysiology.

Nancy Emerson Lombardo
Suzanne and Natalie, how about an animal study using Suzanne's rat models where we look at the effect of specific dietary components on both peripheral and, more important, central (brain-based) IR? And memory or executive function?

Suzanne de la Monte
Animal models and diet? Hmmm. That may be too difficult, but the effects on treating or reducing the depression/dementia markers could be studied.

Natalie Rasgon
I agree with Suzanne; diet is difficult to study in general, and I would think humans would be a better model.

Nancy Emerson Lombardo
At the Bedford VA we have access to AD transgenic animals, and some of the animal researchers are interested in working with me on the diet concept. However we have to design a diet also that looks like the typical American diet that people eat, since the usual mouse chow is actually pretty healthy. But I have to agree with Natalie and Suzanne. Diets are hard to study, period, and I have been learning that if you want to do something more complex than study a single substance, it is very challenging to do in animals. But sometimes the review panels want you to first test anything in animals. In humans, we use dietary guidelines to achieve an overall objective; in animals, they have a precise diet. They eat the same thing at every meal, generally.

June Kinoshita
You can try the Supersize Me diet on the mice.

Natalie Rasgon
What would that be, hamburgers/fries/coke?

Nancy Emerson Lombardo
You are all getting pretty funny, but of course we all are very serious about this! Americans are probably eating (and under-exercising) themselves into depression, IR, and AD as well as heart disease, diabetes, and who knows what else?

Patricia Taylor
How about looking at the difference for a diet that was carbohydrate-loaded versus protein-loaded, or has that already been done?

Natalie Rasgon
I believe there is a need for a number of studies, both in animals and humans. We need to better quantify IR in humans with depressive disorders and we need to test relationships between IR and other neuromarkers in animals and humans.

Nancy Emerson Lombardo
I like June's suggestion about making sure the biomarker and imaging studies now underway—especially the supersize NIA neuroimaging studies—include markers for IR. I think the investigators would be open to this if they haven't already done it.

Suzanne de la Monte
I think the CNS IR story is not simple, as you all probably agree. Just as diabetes can have different severities and adverse effects with regard to peripheral organs, there will have to be a way to look at the CNS selectively. Maybe going back to the depression would be a good one.

June Kinoshita
Speaking of diet, I'm afraid I have to break for lunch. (I'm on South Beach). Please feel free to continue the discussion and hatch a plot to harness Alzforum into furthering this discussion. We're at your service! Hope to hear from you shortly. A transcript will be edited and sent around for corrections. Thank you all very much for today's discussion.

David Ewbank
I have to log off. Dr. Rasgon, thanks for your comments.

Nancy Emerson Lombardo
Thanks, Dr. Rasgon, for another fascinating forum…and Suzanne de la Monte for asking so many great questions. What a treat!

Natalie Rasgon
Great, thanks, all. Susanne and Nancy, looking forward to further interaction!

June Kinoshita
Cheers and bye!

Background

Background

Insulin resistance (IR) is a relatively common metabolic disorder (affecting ~33 percent of the healthy adult population). Insulin is necessary for proper glucose utilization and neuronal survival in the central nervous system, in addition to the peripheral nervous system. Brain glucose deprivation, such as that caused by IR, may underlie the hypometabolic changes observed in crucial brain regions in patients with depression. In those with persistent IR, such changes may progress to more permanent changes characteristic of dementia, especially in those with other risk factors for dementia. We propose that when left undetected and untreated, long-term IR may lead to apoptosis and formation of neuritic plaques and neurofibrillary fibers (NFT), the true hallmark lesions of AD. This is thought to occur via several interactive mechanisms: 1) by affective glucose utilization in insulin-sensitive areas (i.e., limbic structures); 2) by modulating acetylcholine levels in the hippocampus; and 3) by decreasing phosphorylation of the microtubule-associated protein tau (known to play a role in NFT formation). Also, IR furthers cortisol neurotoxicity in the hippocampus, which may be the main mechanism by which changes in endocrine homeostasis affect both mood and cognition.

Read Dr. Rasgon's article in the Journal of Gerontology for details of her intriguing hypothesis. Also of interest is our Live Discussion with Suzanne De la Monte, "Is Alzheimer's a Type 3 Diabetes?."

Topics for discussion:

1) IR in AD and depression
2) IR effects on cognition/memory
3) Potential treatments of AD using insulin-sensitizing medications

Comment by Barry W. Festoff, M.D.—Posted 5 July 2005

My laboratory studied IR in amyotrophic lateral sclerosis (ALS) patients 20 years ago following two decades of anecdotal reports. Using radioactive insulin binding to circulating monocytes and by the euglycemic insulin clamp, we found that insulin receptors were reduced, that a circualting factor, as yet uncharacterized, could account for this reduction and ALS were remarkably insenstive to superphysiologic levels of insulin. These published studies added to other that ultimately resulted in clinical trials using recombinant insulin lije growth factor I (IGF-I) in ALS. A current (third) trial is ongoing.

These studies foreshadowed those seeking to find IR and develop novel treatment approaches in other neurologic diseases.

References:

Reyes ET, Perurena OH, Festoff BW, Jorgensen R, Moore WV. Insulin resistance in amyotrophic lateral sclerosis. J Neurol Sci. 1984 Mar;63(3):317-24. Abstract

Perurena OH, Festoff BW. Reduction in insulin receptors in amyotrophic lateral sclerosis correlates with reduced insulin sensitivity. Neurology. 1987 Aug;37(8):1375-9. Abstract

Ma J, Yang SX, Ho GJ, Festoff BW. Insulin-like growth factor binding protein-1 at mouse neuromuscular synapses. Synapse. 1994 Aug;17(4):225-9. Abstract

Ma J, Yang SX, Ho GJ, Festoff BW. Insulin-like growth factor binding protein-1 is pre-synaptic at mouse neuromuscular synapses and is transported in nerve. Neurochem Res. 1994 Nov;19(11):1363-8. Abstract

Festoff BW, Yang SX, Vaught J, Bryan C, Ma JY. The insulin-like growth factor signaling system and ALS neurotrophic factor treatment strategies. J Neurol Sci. 1995 May;129 Suppl:114-21. Review. Abstract

Hantai D, Akaaboune M, Lagord C, Murawsky M, Houenou LJ, Festoff BW, Vaught JL, Rieger F, Blondet B. Beneficial effects of insulin-like growth factor-I on wobbler mouse motoneuron disease. J Neurol Sci. 1995 May;129 Suppl:122-6. Abstract

Lai EC, Felice KJ, Festoff BW, Gawel MJ, Gelinas DF, Kratz R, Murphy MF, Natter HM, Norris FH, Rudnicki SA. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology. 1997 Dec;49(6):1621-30. Abstract

Festoff BW. The preclinical rationale for the use of insulin-like growth factor-I in amyotrophic lateral sclerosis. Drugs Today (Barc). 1998 Jan;34(1):65-77. Abstract

Arnold, P.M., Ma, J.Y., Smirnova, I.V., Zoubine, M.N., Avery, M.E., Huaibo, S., Citron, B.A. and Festoff, B.W.: Insulin-like growth factor (IGF) binding proteins (IGFBPs) in mouse spinal cord during development. Biochem. Biophys. Res. Comm. 264:652-656, 1999. Abstract

Arnold PM, Ma JY, Citron BA, Zoubine MN, Festoff BW. Selective developmental regulation of gene expression for insulin-like growth factor-binding proteins in mouse spinal cord. Spine. 2000 Jul 15;25(14):1765-70. Abstract

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References

Webinar Citations

1. Insulin Resistance: A Common Axis Linking Alzheimer's, Depression and Metabolism? 6 Jul 2005

News Citations

1. Fish Oil Swims Ahead in Dietary Brain Protection Race 7 Sep 2004
2. Talking Fish Fat And Cholesterol 30 Jul 2003

Paper Citations

1. Reyes ET, Perurena OH, Festoff BW, Jorgensen R, Moore WV. Insulin resistance in amyotrophic lateral sclerosis. J Neurol Sci. 1984 Mar;63(3):317-24. PubMed.
2. Perurena OH, Festoff BW. Reduction in insulin receptors in amyotrophic lateral sclerosis correlates with reduced insulin sensitivity. Neurology. 1987 Aug;37(8):1375-9. PubMed.
3. Ma J, Yang SX, Ho GJ, Festoff BW. Insulin-like growth factor binding protein-1 at mouse neuromuscular synapses. Synapse. 1994 Aug;17(4):225-9. PubMed.
4. Ma J, Yang SX, Ho GJ, Festoff BW. Insulin-like growth factor binding protein-1 is pre-synaptic at mouse neuromuscular synapses and is transported in nerve. Neurochem Res. 1994 Nov;19(11):1363-8. PubMed.
5. Festoff BW, Yang SX, Vaught J, Bryan C, Ma JY. The insulin-like growth factor signaling system and ALS neurotrophic factor treatment strategies. J Neurol Sci. 1995 May;129 Suppl:114-21. PubMed.
6. Hantaï D, Akaaboune M, Lagord C, Murawsky M, Houenou LJ, Festoff BW, Vaught JL, Rieger F, Blondet B. Beneficial effects of insulin-like growth factor-I on wobbler mouse motoneuron disease. J Neurol Sci. 1995 May;129 Suppl:122-6. PubMed.
7. Lai EC, Felice KJ, Festoff BW, Gawel MJ, Gelinas DF, Kratz R, Murphy MF, Natter HM, Norris FH, Rudnicki SA. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology. 1997 Dec;49(6):1621-30. PubMed.
8. Festoff BW. The preclinical rationale for the use of insulin-like growth factor-I in amyotrophic lateral sclerosis. Drugs Today (Barc). 1998 Jan;34(1):65-77. PubMed.
9. Arnold PM, Ma JY, Citron BA, Festoff BW. Insulin-like growth factor binding proteins in cerebrospinal fluid during human development and aging. Biochem Biophys Res Commun. 1999 Nov 2;264(3):652-6. PubMed.
10. Arnold PM, Ma JY, Citron BA, Zoubine MN, Festoff BW. Selective developmental regulation of gene expression for insulin-like growth factor-binding proteins in mouse spinal cord. Spine (Phila Pa 1976). 2000 Jul 15;25(14):1765-70. PubMed.
11. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004 Nov;29(10):1326-34. PubMed.
12. Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006 Mar;27(3):451-8. PubMed.
13. Andersen K, Lolk A, Kragh-Sørensen P, Petersen NE, Green A. Depression and the risk of Alzheimer disease. Epidemiology. 2005 Mar;16(2):233-8. PubMed.
14. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003 Jul;60(7):940-6. PubMed.

Other Citations

1. Dr. Rasgon's article

External Citations

1. Is Alzheimer's a Type 3 Diabetes

Further Reading

No Available Further Reading