Introduction

John P. Blass and Gary Gibson led this live discussion on 15 April 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:
Live discussion held 15 April 2002.

Participants: John Blass, Gary Gibson, Paula Grammas, Glenda Bishop, Mark Smith, Alexei Koudinov, Siegfried Hoyer, Gabrielle Strobel.

Note: The transcript has been edited for clarity and accuracy.

Paula Grammas: Hi.

Gabrielle Strobel: Hi. It's Patriot's Day here in Massachusetts. The brass bands are thumping and mock Minutemen are shooting outside my house. Good thing this is not a phone chat.

John Blass: Hi!

Mark Smith: Here I am! Great topic for discussion . . . am looking forward to this.

Gabrielle Strobel: Welcome, John. We'll give everyone a few more minutes to log on. Hi Mark!

Glenda Bishop: Hello.

Gabrielle Strobel: Hello and welcome everyone. As a start, let me ask John: what exactly do you mean by insufficient brain metabolism being the proximate cause of AD? Do you mean other factors bring on a disease process, as for example accumulation of amyloid and hyperphosphorylated tau, but metabolic problems immediately precede, and thus trigger, clinical symptoms?

Gary Gibson: Your statement is accurate. But in other situations perturbed metabolism could cause the symptoms and the pathology.

Gabrielle Strobel: In which situations? Can you give us some examples?

John Blass: My assumption is that a variety of ills lead to Alzheimer's disease, which is defined as a particular pattern of brain scarring--plaques and tangles, neuronal shrinkage and/or drop out, as well as other changes. However, only about half of the people who have classic pathology are clinically demented (see Polvikoski et al., 2001). Only once the metabolic lesion develops in patients who have Alzheimer's pathology do they become mentally impaired. Therefore, the metabolic insufficiency is the "proximate cause" of the clinical syndrome.

Glenda Bishop: I would like to know whether you are suggesting that metabolic insufficiency leads to AD pathology or whether AD pathology leads to metabolic insufficiency.

Gary Gibson: Plaques occur in patients with mitochondrial disease. Tangles occur in patients with Wernicke-Korsakoff syndrome (Kril, 1996). Thus, precedent exists for metabolic insufficiency causing the pathology.

Alexei Koudinov: And tangles also occur in Parkinson’s and ALS, see (Koudinov & Koudinova 2002).

Mark Smith: Therefore, plaques and tangles are secondary?

Glenda Bishop: Is there evidence of metabolic insufficiency without plaques and tangles?

John Blass: If you have metabolic insufficiency without plaques and tangles, you will have cognitive impairment, i.e. dementia, but by definition it will not be AD without those anatomical lesions.

Gary Gibson: There are many cases of metabolic insufficiency without plaques and tangles (metabolic encephalopathies), and all have reduced mental function.

Glenda Bishop: Does the dementia have the same symptoms of AD even though the "necessary" pathology is not there?

John Blass: "Same" is a tricky word. Near enough that excellent clinicians can generally not tell the difference, at least in my experience.

Gary Gibson: Glenda, these are of course not identical. But they have many similarities. For example, the cholinergic system is depressed in both.

Gary Gibson: Glenda, the close coupling of metabolism and acetylcholine suggest that even cholinesterase inhibitor therapies may be directed to the metabolic lesion.

Mark Smith: John, this looks like a problem with the definition of AD. One that sets up a straw man for plaques and tangles. But even this straw man has problems, i.e., the lesions that develop with age.

Alexei Koudinov: And should we then call cardiovascular patients, who develop amyloid in the brain AD patients? See Sparks et al., 1990.

Glenda Bishop: But then are any two AD cases really identical? Even with the required pathology.

Gary Gibson: What do you mean by identical?

Glenda Bishop: Same numbers of plaques/tangles, and correlation of this pathology with dementia severity.

John Blass: No two people are identical, and no two patients are identical. (That's what makes clinical medicine fun.) They are similar enough, one hopes, that experience with one can help to guide treatment for the other. For instance, two patients with pneumonia may both respond to penicillin even though they are not "alike."

Paula Grammas: Guys, can you further clarify metabolic insufficiency? We debated the chicken-egg timing of vascular dysfunction and neuronal dysfunction in Cincinnati, but is vascular impairment under the rubric here of metabolic insufficiency?

John Blass: "Metabolic insufficiency" means that the rate at which the brain can metabolize its major substrate (normally glucose) is inadequate to meet the demands of the tissue for maintaining structure and function.

Gabrielle Strobel: John and Gary, what are those treatments/trials of brain metabolism and the preliminary results you mention in your background text?

Gary Gibson: In one study John and I published, the correlation of clinical state with a mitochondrial enzyme was 0.7 while that with plaques and tangles was 0.2 or less. (Gibson et al., 2000)

Mark Smith: Getting back to Glenda's question regarding primary versus secondary, our data, as well as John and Gary's, certainly indicates metabolic insufficiency is a very early event . . . any earlier and the people are controls! Although, related to this, ApoE4 carriers show reduced brain metabolism.

Glenda Bishop: So if this insufficiency comes first, have any studies shown that it can lead to plaque deposition/tangle formation?

Gary Gibson: There are at least the two situations in people: MELAS (Rothman, 1999) and Wernicke-Korsakoff. Also there are several reports that interfering with metabolism increases amyloidogenic fragments intracellularly.

John Blass: Studies we and others did in the 1980s and early 1990s showed that impairing energy metabolism could lead to cytoskeletal disorganization and increased AβPP expression. (Koh et al., 1990)

Alexei Koudinov: George Perry proposed long ago that the break in normal neuronal cytoskeleton may be related to normal neurofilaments being substituted abnormal paired helical filaments composed of abnormally phosphorylated tau (Perry et al., 1991.)

Glenda Bishop: Does the increased AβPP expression actually precipitate Ab deposition?

Mark Smith: In mice it does!

John Blass: Mark, what does?

Mark Smith: Over-expression of AβPP leads to Aβ deposition in mice.

Glenda Bishop: No. In mice it does not. They get increased AβPP but not actual Aβ deposition, at least in studies of neuronal damage.

Mark Smith: NOT TRUE...what about Karen's mice?

Glenda Bishop: They are engineered to over-express. I meant normal mice.

Mark Smith: Ok, nut normal mice do not over-express, at least chronically.

Mark Smith: Back to the metabolic issue. I think there is enough evidence now that attacking this therapeutically will be of benefit, which is certainly better than one can say about attacking Aβ!

John Blass: Mark as usual puts his finger on the issue. What matters is less what the "prime mover" of AD is than what we can do to help.

Glenda Bishop: AβPP expression can be induced in normal mice by instances of damage.

John Blass: AβPP is increased as a result of a variety of insults to the brain--not only hypoxia/ischemia but also even head trauma. It seems more likely that this mechanism has evolved to protect the brain than to harm it. In other words, AβPP and its products may be signs of chronic damage as well as--or more than--causes of damage.

Glenda Bishop: I agree with you completely!

Mark Smith: Exactly, John! That's why the vaccine was a disaster.

Glenda Bishop: So if we can target the damage, we can remove the problem.

Mark Smith: Glenda, I think so, at least based on epidemiological evidence.

Gabrielle Strobel: What sorts of treatments will reduce the damage/insufficiencies?

Mark Smith: Rob Friedland in Cleveland has data on exercise, diet, head trauma.

John Blass: Thanks! Mark, do you think the vaccine-related damage was due primarily to an inflammatory infiltrate or primarily to loss of a protective effect of AβPP?

Glenda Bishop: I pick loss of AβPP.

Mark Smith: John: I would bet on the loss of Aβ/AβPP.

Gabrielle Strobel: Apparently people with the inflammation did not have high antibody titers but did have a T cell response.

Glenda Bishop: Where was the info about the antibody titers?

Gabrielle Strobel: Dale Schenk mentioned it at last month's Ipsen meeting in Paris. See conference summary.

Paula Grammas: But cranking up the inflammatory response in late AD people has to play a role.

Gary Gibson: Impaired metabolism can paradoxically increase oxidative stress. Thus, reducing oxidative stress is one good therapeutic target, and this was likely increased in the inflammatory response.

Gabrielle Strobel: Regarding the mitochondrial alpha-ketoglutarate dehydrogenase complex: Gary and John, you wrote in 1999 about its reduced activity in AD brains and in 2000 about its link to ApoE4. Can you explain the latter? Do you suggest that ApoE4's effects (presumably altered cholesterol transport) bring on early AD via mitochondrial damage?

Gary Gibson: The connection is more likely related to ApoE modulating oxidative stress. KGDHC is very sensitive to oxidative stress.

John Blass: ApoE alleles differ in their composition of cysteines relative to arginines, and therefore in their ability to act as free-radical quenchers. Like Gary, I suspect that the role of ApoE4 as a risk factor in many diseases relates to its being a less effective antioxidant than ApoE3 or ApoE2.

Paula Grammas: But ApoE4 fragments also have neurotoxic properties.

Gabrielle Strobel: Are the molecular links involving mitochondria and AD becoming clear? I am very nebulous on that.

Gary Gibson: In some cases it may be genetic, but none are well established. Both PS and AβPP mutations can act through mitochondria.

Mark Smith: The mitochondrial link to oxidative stress is akin to the chicken-and-egg problem: targeting either will ultimately benefit patients.

Gabrielle Strobel: How does KGDHC tie into toxicity/stress factors on the one hand, and metabolic problems/neuronal death on the other? Are any molecular pathways emerging?

Glenda Bishop: Gary, are you suggesting that oxidative stress occurs (maybe due to ApoE4), and then KGDHC activity is decreased, and that causes enough insufficiency to precipitate dementia symptoms?

Gary Gibson: That is our working hypothesis. No pathways yet.

Alexei Koudinov: How would you connect your point on different activities of ApoE alleles with antioxidant activity of Ab reported by the Beisiegel/Kontush group and Ashley Bush's team? (Kontush, 1999; Lynch et al., 2000).

John Blass: AβPP and Aβ have antioxidant (ROS-quenching) ability due to the ready oxidizability of the Met-35 on the Ab peptide.

Mark Smith: I agree with Gary completely--the problem is that everyone uses the distal readout of Aβ as being the important factor. Also Aβ binds copper to act as a superoxide dismutase (Curtain et al., 2001; see also Ashley Bush's comment).

John Blass: Free radicals are signal compounds as well as damaging agents. The fundamental problem in AD may be a resetting of metabolism at too low a level to allow the brain to age in a healthy way.

Alexei Koudinov: That is a very good point. And, Mark, I would like to thank you and your colleagues for Joseph et al, 2001.

Mark Smith: Alexei, this and our other anti-Aβ attacks have not gone down well with members of the Church of the Holy Amyloid!

Gabrielle Strobel: KGDHC is no drug target, right? It is easier to block an enzyme than to boost its function. Could polymorphisms become a marker for vulnerability to develop dementia?

John Blass: Gabrielle, that has been our hope, but the data we have generated on polymorphisms of KGDHC components is hardly compelling.

Gary Gibson: Actually, in many cases KGDHC is inactivated, not missing. Reactivating it is a reasonable target.

Glenda Bishop: How exactly is it deactivated? Is there a modification to the enzyme?

Gary Gibson: Glenda, this is a focus of our current research.

Glenda Bishop: So all you know right now is that the activity is decreased but the protein level is consistent?

Gary Gibson: Correct, we know how to inactivate the enzyme in cells and when purified. But not how it is inactivated in AD brain.

Glenda Bishop: How do you inactivate, then? Free radical attack?

Gary Gibson: We inactivate with NO peroxynitrite and oxygen species generated by H2O2.

Gabrielle Strobel: What kinds of therapies are conceivable based on your hypothesis?

John Blass: Gabrielle, Manning, Gold and coworkers, and Susanne Craft and coworkers, have shown transient memory improvements in AD patients by raising blood glucose to the low diabetic level. My colleagues and I have been trying a mixture of metabolites--glucose plus--in clinical trials. The results of open trials were very encouraging, and a double-blind trial is now in progress.

Gabrielle Strobel: Is this published?

John Blass: Gabrielle--I think so, but I'm not sure. To be up front, it's patented, and Cornell devolved the patent onto me (they felt there's no money in it).

Mark Smith: Gabrielle, therapies should target primary aspects of the disease (metabolism, oxidative stress) rather than downstream consequences (tau and amyloid). The goal is to prevent AD and to do this is a matter of healthy living (exercise, diet, cholesterol). Once you have the disease, these may be too late.

Gary Gibson: Agreed.

Alexei Koudinov: Mark, we agree with you, see (Koudinov & Koudinova, 2002).

Mark Smith: Alexei, great. Prepare yourself for lean times on the funding front! Alexei Koudinov: We'll see. Thus far I have nothing to lose

Gabrielle Strobel: Exercise, diet, cholesterol help prevent heart disease, stroke, diabetes, general age-related decline. What is the specific link to AD?

Paula Grammas: Mark hear, hear. Seems all the good stuff, i.e. exercise, diet, cholesterol relate to vascular disease.

Glenda Bishop: Healthy living relates to vascular and all diseases. Is AD any different, then?

Mark Smith: Vascular disease is likely a key contributor to the issues we are talking about today.

Paula Grammas: Vascular relates to several diseases. But most of these risk factors are most clearly defined for vascular changes.

John Blass: Again, let me agree. As Alzheimer and his friends pointed out, vascular disease is a risk factor for "senile dementia," presumably via its effects on metabolism, including free radicals. Wouldn't it be wonderful to have a therapy that benefited both the neurodegenerative and vascular components of dementia?

Gabrielle Strobel: So one treatment approach is raising brain glucose levels. Sounds simple enough.

Mark Smith: Gabrielle, and doing so does have a profound impact on cognition, at least short-term.

Gary Gibson: Gabrielle, Paul Gold has shown that high glucose therapy also seems to work through cholinergic mechanisms (Ragozzini et al., 1998).

Gabrielle Strobel: That is interesting. I look forward to reading up on this approach. How about antioxidants? Have not some been tried, and mostly failed, such as vitamin E?

Gary Gibson: Gabrielle, One difficulty with antioxidants is that they are readily converted to oxidants. Thus, designing the right one may be difficult.

Gabrielle Strobel: Some drugs are being developed to stabilize mitochondrial function, for example, some polycyclic phenols. Do you know anything about those?

Paula Grammas: What about combination therapies, statins, glucose, antioxidants? Anyone taking that approach?

John Blass: In practice, most diseases are treated with combination therapies--for instance, antihistaminics, anti-inflammatories, an expectorant, and sometimes an antibiotic for an upper respiratory infection. There is no conceptual difficulty in treating dementia with a variety of agents.

Gabrielle Strobel: Did you all see Siegfried Hoyer's comment? He wrote about insulin dysregulation. How does this hypothesis fit into the picture of oxidative stress and mitochondrial damage?

John Blass: Suzanne Craft also is interested in the insulin hypothesis. My understanding is that there are a limited number of specific cells in the hippocampus that, unlike other brain cells, require insulin for efficient entry of glucose. These cells may be intimately involved in the memory problems in AD (Craft et al, 1996; Craft et al, 1993).

Gary Gibson: Most perturbations of normal metabolism, including insulin metabolism, lead to increased oxidative stress.

Gabrielle Strobel: On a side note: How does your hypothesis fit with epidemiological reports of high cognitive activity creating a 'reservoir' of sorts that protects for a while from manifestation of AD symptoms? Do these people inherit 'more active' metabolic enzyme variants? Or do they keep them highly expressed, much like moderate drinkers have higher protein levels of alcohol-degrading enzymes?

John Blass: That's a reasonable model. Unfortunately, we have no direct data.

Gary Gibson: If our hypothesis is correct, your interpretation would provide a convenient explanation.

Glenda Bishop: If AD is caused by metabolic problems, then there must be a reason why some people develop these problems, since not everyone gets AD. The question then is the initial trigger of the problems.

John Blass: I've tried, in print, to make a distinction between Alzheimer's disease (the neuropathological entity) and Alzheimer dementia (clinical dementia in an individual with Alzheimer Disease). For me, as a still some-time clinician, the problem of the dementia is much more interesting than that of the "primary cause" of the pathology.

Glenda Bishop: John, that was a very interesting commentary you wrote, by the way. Hopefully they will publish it soon.

John Blass: Thanks! [Editor: An exchange of commentaries between Stephen Robinson and Glenda Bishop on the one hand, and John Blass on the other will appear in an upcoming issue of Neurobiology of Aging .]

Alexei Koudinov: In my view these two set of questions allow us to think about what are the differences between AD and PD, AD and ALS, etc. I also think today's subject is related to the discussion we had a week ago on synaptic plasticity changes in the disease, as one issue is closely related to the other.

Mark Smith: Sorry, got to go to a meeting. Thanks to all and keep up the good fight!

Gabrielle Strobel: Bye Mark, and thanks. Since the hour is winding down, I would like to give our two lead panelists the chance to make a wish list. What would you like to see done so your hypothesis can be definitively tested, and/or advanced into the clinic?

Gary Gibson: The hope would be to find a way to reactivate energy in AD brain.

John Blass: My dearest wish is to find an effective way to modify the metabolic deficiency in AD.

Alexei Koudinov: Thanks a lot... I just wish there were more participants. Thanks a lot to all. Dinnertime in the Middle East.

Glenda Bishop: I have to go. Thanks for the chat.

Paula Grammas: Also have to go, bye to all and thanks

Siegfried Hoyer: Good afternoon, everybody.

Gabrielle Strobel: Hi Dr. Hoyer, you are joining us as the discussion is winding down. Do you have any last-minute questions for John and Gary?

Gary Gibson: Siegfried, I think they forgot to tell you the US switched to daylight savings time last Sunday.

Siegfried Hoyer: Hello Gary, what's new and exciting in AD-research?

Gabrielle Strobel: You and Dr. Hoyer can continue this discussion for as long as you like.

John Blass: Unfortunately, I must also sign off and miss the chance to have yet another enlightening discussion with Siegfried. My loss!

Gabrielle Strobel: I want to thank you all very much for a stimulating discussion. I will circulate the transcript to you for review. See you again another time!

Siegfried Hoyer: What was the reaction to my comment?

Gabrielle Strobel: People said that insulin dysregulation may increase oxidative stress and thereby damage mitochondria. How could your hypothesis be definitively tested? What should happen next?

Siegfried Hoyer: The insulin-dependent reactions I suspect of playing a role in AD must be tested in vitro and in vivo, including in post-mortem tissue. We have conducted animal experiments that support our hypothesis.

Gabrielle Strobel: Insulin resistance and type-two diabetes are difficult to treat long-term. Which treatment methods does our hypothesis suggest for AD?

Siegfried Hoyer: The problem in AD is really the same as in treating type-2 diabetes. Initial results of treating AD patients with mixed glucose/insulin infusions are positive. Here are some references about this and another treatment and the general hypothesis: Boyt et al, 2000; Lannert & Hoyer, 1998; Hoyer et al., 1999; Hoyer, 2002.

Gabrielle Strobel: It's time to fix lunch for my kids now. Please do come back to our next chats.

Siegfried Hoyer: Sorry for being so late. Auf Wiedersehen.

Background

Background Text
By John P. Blass and Gary Gibson, Weill Cornell College of Medicine

Our group has proposed that the cerebrometabolic deficiency in Alzheimer's disease(AD) is the proximate cause of the clinical disability. Several sets of observations support this hypothesis.

1. Impaired brain metabolism essentially always occurs in clinically significant AD, and the degree of clinical disability is proportional to the degree of metabolic impairment. The earliest, mildest changes in brain metabolism occur even before the onset of measurable cognitive impairment or atrophy. This observation disproves the now outdated assumption that the decreased metabolism is simply a consequence of decreased mental function or of atrophy. One of the important mechanisms reducing brain metabolism in AD appears to be damage to key mitochondrial components.

2. Inducing impairments of brain metabolism causes changes in mentation that mimic the clinical disabilities in AD, in both humans and experimental animals.

3. Preliminary results from several units suggest that treatment directed at the impairment of brain metabolism can improve neuropsychological functions in AD patients. This hypothesis does not negate the importance of other mechanisms in AD, such as amyloid accumulation, vascular compromise, and free radical action. However, those other abnormalities can occur in people whose mentation is still clinically unimpaired. Approximately half the people over the age of 85 who have the full panoply of the neuropathology of AD are clinically well. The frequently-advanced hypothesis that they would have developed dementia "if they had lived long enough" is not testable. In contrast, once significant decrease in the rate of brain metabolism occurs, mentation essentially invariably becomes defective. That statement is supported by robust experimental observations in both humans and other animals.

References
1. Snowden DA. Aging and Alzheimer's disease: Lessons from the Nun study. Gerontologist 1997;(37):150-156. Abstract.

2. Blass JP. Immunological treatment of Alzheimer's disease. New Eng J Med 1999;(22):1694-1695. Abstract.

3. Robinson SR, Bishop GM. A-β as a bioflocculant: implications for the amyloid hypothesis of Alzheimer's disease. Neurobiol Aging, in press.

4. Gibson GE, Park LC, Zhang H, Sorbi S, Calingasan NY. Oxidative stress and a key metabolic enzyme in Alzheimer brains, cultured cells, and an animal model of chronic oxidative deficits. Ann N Y Acad Sci 1999;(893):79-94. Abstract.

5. Gibson GE, Blass JP. Metabolism and neurotransmission. In Handbook of Neurochemistry, A. Lajtha ed, Vol. 3, 2nd Ed. Plenum Press, New York, 1982, pp. 633-651.

6. Blass JP, Gibson GE. Cerebrometabolic aspects of delirium in relationship to dementia. Dement Geriatr Cogn Disord 1999;(10):335-338. Abstract.

7. Hirsch JA, Gibson GE. Selective alteration of neurotransmitter release by low oxygen in vitro. Neurochem Res 1984;(9):1039-1049. Abstract.

8. Blass JP. Pathophysiology of the Alzheimer's syndrome. Neurology 1993;(43):S25-S38.

9. Blass JP. The mitochondrial spiral: An adequate cause of dementia in the Alzheimer syndrome. Ann NY Acad Sci 2000;(924):170-183. Abstract.

10. Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999;(222):236-245. Abstract.

11. Frey KA, Minoshima S, Kuhl DE. Neurochemical imaging of Alzheimer's disease and other degenerative dementias. Q J Nucl Med 1998;(42):166-168. Abstract.

12. de Leon MJ, Convit A, Wolf OT, Tarshish CY, DeSanti S, Rusinek H, Tsui W, Kandil E, Schere H, Roche A, Imossi A, Thorn E, Bobinski M, Caraos C, Lesbre P, Schyler D, Poirier J, Resiberg B, Fowler J. Prediction of cognitive decline in normal elderly subjects with 2-[18F]fluoro-2-deoxyglucose/positron-emission tomography (FDC/PET). Proc Natl Acad Sci USA 2001;(98):10966-10971. Abstract.

13. Kumar A, Schapiro MB, Grady G, Haxby JV, Wagner E, Salerno JA, Friedland RP, Rapoport SI. High resolution PET studies in Alzheimer's disease. Neuropsychopharmacology 1991;(4):35-46. Abstract.

14. Fukuyama H, Ogawa M, Yamauchi H, Yamaguchi S, Kimura J, Yonekura Y, Konishi J. Altered cerebral energy metabolism in Alzheimer's disease: A PET study. J Nuclear Med 1994;(35):1-6. Abstract.

15. Frolich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humfrich J, Laufer S, Muschner D, Thalheimer A, Trk A, Hoyer S, Zchling R, Boissl KW, Jellinger K, Riederer O. Insulin and insulin receptors in the brain in aging and sporadic Alzheimer's disease. J Neural Transm 1998;(105):423-438. Abstract.

16. Henneberg N, Hoyer S. Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)? Arch Gerontol Geriatr 1995;(21):63-74.

17. Hoyer S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm 1998;(105):415-422. Abstract.

18. Sorbi S, Bird ED, Blass JP. Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 1983;(13):72-78. Abstract.

19. Gibson GE, Sheu K-FR, Blass JP. Abnormalities of mitochondrial enzymes in Alzheimer disease. J Neural Transmission 1998;(105):855-870. Abstract.

20. Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q, Lesser M, Mohs RC, Sheu RK-F, Blass JP, Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. Ann Neurol 2000;(48):297-303. Abstract.

21. Kish SJ, Mastrogiacomo F, Guttman M, Furukawa Y, Taanman JW, Dozic S, Pandolfo M, Lam L, Distefano L, Chang LJ. Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer's disease and hereditary spinocerebellar ataxia disorders: a nonspecific change? J Neurochem 1999;(72):700-707. Abstract.

22. Sheu K-FR, Blass JP. The a-ketoglutarate dehydrogenase complex. Ann NY Acad Sci 1999;(893):61-78. Abstract.

23. Blass JP, Sheu K-FR, Piacentini S, Sorbi S. Inherent abnormalities in oxidative metabolism in AD: Interaction with vascular abnormalities. Ann NY Acad Sci 1997;(826):382-385. Abstract.

24. Calingasan NY, Baker H, Sheu K-F, Gibson GE. Distribution of the a-ketoglutarate dehydrogenase complex in rat brain. J Comp Neurol 1994;(346):461-479. Abstract.

25. Ko L, Sheu K-FR, Thaler HT, Markesbery WR, Blass JP. Selective loss of KGDHC-enriched neurons in Alzheimer temporal cortex: does mitochondrial variation contribute to selective vulnerability? J Molec Neurosci 2001;(17):361-369. Abstract.

26. Curti D, Rognoni F, Gasparini L, Cattaneo A, Paolillo M, Racchi M, Zanni L, Bianchetti A, Trabucci A, Bergamaschi S, Govoni S. Oxidative metabolism in cultured fibroblasts from sporadic Alzheimer's disease. Neurosci Lett 1997;(236):13-16. Abstract.

27. Butterfield DA, Yatin SM, Link CD. In vitro and in vivo protein oxidation induced by Alzheimer's disease amyloid beta-peptide (1-42). Ann NY Acad Sci 1999;(42):265-268. Abstract.

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  1. "A central issue in medicine is the grouping of disorders on the basis of their etiology, yet one common clinico-pathologic feature of diseases does not indicate a common etiology. Therefore, from a nosological point of view, Alzheimer's disease is no one single disorder. Rather, type I/ disease I is due to mutation within three genes (5 percent of all AD cases); whereas type II/ disease II is sporadic in origin without any mutations (95 percent of cases). Both susceptibility genes and adult life-style risk factors, such as aging, participate in the origin of the latter AD type. Thus, I fully support the view of John Blass and Gary Gibson that sporadic AD is an age-associated cerebrometabolic disorder.

    It appears necessary to make a clear distinction between these two heterogenous pathologic conditions. In its early pathogenesis, perhaps in its etiology, normal functions of insulin and insulin signal transduction were found to be severely perturbed in the brain, causing acetylcholine reduction, an ATP deficit, disturbed AbPP trafficking in the endoplasmic reticulum and Golgi apparatus, tau hyperphosphorylation, and reduced activities of enzymes associated with the cell cycle." -Siegfried Hoyer, University of Heidelberg, Germany.

  2. Of course, metabolism and function are the two faces of a coin. But metabolic failure exists not only in Alzheimer's disease, but in any brain disease. So, if we want to define the disease we must use the peculiar characteristics (NFT and so on) and not the metabolism.

References

Webinar Citations

  1. Cerebrometabolic Deficiency in Alzheimer's Disease

News Citations

  1. Conference Coverage: IPSEN Foundation
  2. Synaptic Zinc Fingered As Critical In Plaque Formation

External Citations

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  24. Polvikoski et al., 2001
  25. Kril, 1996
  26. Koudinov & Koudinova 2002
  27. Sparks et al., 1990
  28. (Gibson et al., 2000)
  29. Rothman, 1999
  30. (Koh et al., 1990)
  31. Perry et al., 1991.
  32. Kontush, 1999
  33. Lynch et al., 2000
  34. Curtain et al., 2001
  35. Joseph et al, 2001
  36. Koudinov & Koudinova, 2002
  37. Ragozzini et al., 1998
  38. Craft et al, 1996
  39. Craft et al, 1993
  40. Boyt et al, 2000
  41. Lannert & Hoyer, 1998
  42. Hoyer et al., 1999
  43. Hoyer, 2002

Further Reading

Papers

  1. . Neuron loss in APP transgenic mice. Nature. 1998 Oct 22;395(6704):755-6. PubMed.