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Alexei R. Koudinov and Natalia V. Koudinova
Brain cholesterol pathology is the cause of Alzheimer's disease
clinmed/2001100005v1 [Abstract] [Full text]

Electronic letters published:

[Read eLetter] COMMENTS ON CHOLESTEROL AS THE CAUSE OF ALZHEIMER’S DISEASE
Ming Chen   (11 January 2002)
[Read eLetter] Alzheimer's Disease Byophysical Semeiotics supports the pathophysiology of Koudiniv's theory.
Stagnaro Sergio   (11 January 2002)
[Read eLetter] Behind tau and amyloid beta in AD's pathogenesis.
Sergio Stagnaro   (11 January 2002)

COMMENTS ON CHOLESTEROL AS THE CAUSE OF ALZHEIMER’S DISEASE 11 January 2002
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Ming Chen,
Medical Researcher
VA Medical Center and University of South Florida

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Re: COMMENTS ON CHOLESTEROL AS THE CAUSE OF ALZHEIMER’S DISEASE

michen{at}hsc.usf.edu Ming Chen

Based on their experimental data, Koudinov and Koudinova (1) have proposed that “brain cholesterol pathology is the cause of Alzheimer’s disease” (AD). At the same time, however, several other factors such as plaques, tangles, free radicals, metal imbalance, or apoptosis, have also been widely thought to be the primary reasons for neuronal death in late- onset AD. It appears to me that these proposals are similar in general concept, but only differ in the individual lesions as primary suspects.

But logically, if any factor is assumed to be the primary suspect in AD, then it would be necessary to answer the following three questions that I consider to be of paramount importance in AD research:

(a) Where does it come from?

Cholesterol deposition (and also plaque, tangle, free radical, etc.) is a common feature of the aging brain, thus to say “cholesterol is the cause of AD” would be the same as to say “aging is the cause of AD”. Apparently, this view does not explain the second feature of the disease:

(b) Why do only some elderly, but not others, develop AD?

If all elderly have cholesterol and plaque depositions, but only some of them develop AD, then it would be reasonable to assume that something else in the patients, but not cholesterol or plaque only, is more important for cell death in AD. But what is it? To this difficult question, here we consider a similar situation: all elderly have atherosclerosis and bone loss, but why do only some of them suffer from heart attack and severe osteoporosis at the same old age? We know that this is mainly due to the so-called “risk factors” in life, such as lifestyle, diet, and personal background. They together can make a difference.

Thus, by taking these other senile disorders as role models, our answer to the questions (a) and (b) would be: aging, enhanced by risk factors (lack of exercise, certain diets, social isolation, low brain reserve and education, etc.), are perhaps responsible for late-onset sporadic AD. (note that this type of AD does not include early-onset and familial AD, vascular dementia, and head injury or HIV-related dementia).

(c) However, this model has not explained yet another basic question: elderly and risk factors always exist throughout human history, but why only very recently has AD become a severe social threat?

We all know that this is simply because the elderly used to live to ages 60 and 70s, but today many of them to 80 and 90s. This unprecedented longevity is the result of medial progress, but also is the ultimate reason for the widespread of AD today (and also for many other senile disorders).

Therefore, by considering the above three questions altogether, I propose that “advanced aging (typically after age 80) plus risk factors ultimately underlie late-onset sporadic AD”. This model may be more encompassing than attributing the cause of AD to any one individual lesion (cholesterol, plaque, tangle, free radical, etc) in that it points to the intervention strategies to be primarily the risk factors. At the same time, it also suggests that targeting cholesterol, plaque, tangles, free radicals, or metal imbalance, etc. may also help in our endeavor – in much the same way as what we have done to the old bones and muscles. This model has been discussed in more detail in our three recent articles (2- 4).

References:

1. Koudinov, AR, Koudinova, NV. Clin Med Health Res (2001) clinmed/2001100005

2. Chen, M, Fernandez HL. Where do Alzheimer's plaques and tangles come from? Aging-induced protein degradation inefficiency. Front Biosci (2001) 6, e1-11. (Abstract links to full text)

3. Chen, M, Fernandez, HL. Revisiting Alzheimer's disease from a new perspective: Can “risk factors” play a key role? J. Alzheimer’s dis. (2001) 2, 97-108. Abstract (http://www.j-alz.com/vol2_number2.html)

4. Chen, M, Fernandez, H.L. Alzheimer movement re-examined 25 years later: is it a "disease" or a "senile condition" in medical nature? Front Biosci (2001) 6, e30-40 (Abstract links to full text: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11502485&dopt=Abstract)

Sincerely yours,

Ming Chen, Ph.D.)

Alzheimer's Disease Byophysical Semeiotics supports the pathophysiology of Koudiniv's theory. 11 January 2002
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Stagnaro Sergio,
Specialist in Blood, Gastrointestinal, and Metabolic Diseases
Retired. Research in Biophysical Semeiotics.

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Re: Alzheimer's Disease Byophysical Semeiotics supports the pathophysiology of Koudiniv's theory.

dottsergio{at}libero.it Stagnaro Sergio

Sirs, in a previous paper (http://digilander.iol.it/semeioticabiofisica) I described an original biophysical semeiotic method, easy to apply at the bed si-de and reliable in recognizing Alzheimer’s Disease, even in initial and/or symptomless stage (See later on). I agree with R Kale (1) who wrote that “tackling the problems posed by the neurodegenerative disorders is difficult. We could draw inspiration from the former US president (R. Reagan) who survived falls from horses, cancer of the skin and colon, and a bullet in the chest and is now quietly battling Alzheimer's”. However, even in such neurodegenerative disorders, in my opinion, we must aim to the early “clinical” diagnosis, possibly soon after disease on-set, or better in the so-called “pre-pathological” phase, i.e. “real” risk of disease. Morover, the diagnosis must be necessarily “clinical”, because GPs, who at first visit these patients, have to recognize the initial or “pre-pathological” stages, characterized by modification of Neuronal and Cerebral Evoked Potentials, nowadays assessed bed-side by means of Biophysical Semeiotics (See: Cerebral Tumour, in htt://digilander.iol.it/semeioticabiofisica). As I have written earlier in a Rapid Response on bmj.com (16 June 2001), during an early biophysical-semeiotic research (2, 3), briefly referred in the above -cited site: Page: “Early clinical biophysical-semeiotic Diagnosis of Alzheimer’s Disease”, I gathered interesting data, due to the fact that there is notoriously an association between high serum cholesterol, raised blood pressure and, finally, -insulin-resistance. Briefly, in healthy, from the microcirculatory point of view, during stress test both vasomotility (chaotic-deterministic oscillations of arterioles) and vasomotility (chaotic-deterministic fluctuations of nutritional capillaries and post-capillary venules) particularly in hippocampus, pre- frontal and parietal cerebral regions are maximally activated. (2, 3, 4, 5). On the contrary, in individuals with a family history positive for Alzheimer’s disease and, of course, in patients in the first stages, under identical conditions appears a particular form of microcirculatory activation, characterized by increased vasomotility and decreased vasomotion (I termed it dissociated type). In a few words, the flow- and flux-motion in the cerebral microcirculatory bed appears to be clearly decreased, due to the dangerous phenomenon of the so -called “microcirculatory blood-flow centralization”. Unfortunately, it is generally admitted that diagnosing Alzheimer’s disease, particularly in initial stages, is very difficult. In my 44-year-long clinical experience the test of acute pick of insulin secretion (2, 3) proved to be reliable in bed-side recognizing this (and other numerous) disorder, even in its first stage. Although insulin isn’t necessary in the glucose utilizations of cerebral neurons, surely in both cerebral cortex and hippocampus there is a largely amounts of insulin receptors (6). In initial stages of the disease has been demonstrated a scarse glucose metabolism in cerebral tissue: venous glucose level appears to be slightly decreased (6). The authors, in addition, demonstrated that O2 consumption is unchanged, due to the fact that the neurons utilize other “endocellular” substances rather than glucose, probably causing neurons death (7). Although insulin isn’t necessary in glucose utilizations of cerebral neurons, however in both cerebral cortex and hippocampus there is surely a largely amounts of insulin receptors (6). In addition, in the initial stages of the disease has been demonstrated a scarse glucose metabolism in cerebral tissue: venous glucose level appears to be slightly decreased (6). These authors, moreover, demonstrated that O2 consumption is unchanged, due to the fact that the neurons utilize other “endocellular” substances rather than glucose, probably causing neurons death. In summary, in the complex and non completely understood pathophysiology of Alzheimer’s disease does exist a fault response of cerebral insulin receptors, while the hormon acts likily as a growth factor. From these work hypothesis, in a previous clinical research I observed that acute pick of insulin secretion (2, 3, 4) in healthy activates the microcirculation in all biological systems, while in patients at “real” risk of Alzheimer’s disease and, naturally, in patients involved by the disease, even in early stage, microcirculatory activation is totally absent. Importantly as well as interestingly, in no other cerebral disorders, including cerebral arteriosclerosis, I did observe the absence of insulin-receptors response, i.e. the absense of microcirculatory activation, type I, associated. From the above remarks, I consider that A.R. Koudinov’s et al. theory (I got unfortunately acquainted with it recently, since 1st December 2001 ) according to which cholesterol is implicated in Alzheimer's disease (AD) (8). In fact, their own recent studies show that accurate neuronal cholesterol dynamics is critical for the synaptic plasticity and neural degeneration. These data also imply the link between neuronal lipid metabolism and tau and amyloid beta neurochemistry and propose that the classical AD brain lesions are functional consequences of the neuronal cholesterol and possibly phospholipid biological misregulation. In addition, I think that also insulin-receptors are less responsiv to insulin under such circumstances, as I demonstrated in my research.In my opinion, we have to pay all attention to this intriguing theory, that finally enlightens the physiopathology of the biophysical-semeiotic manoeuvre, specific in diagnosing AD, even in early pre-clinical stage.

Yours, Stagnaro Sergio MD., Member NYAS and AAAS

1) Kale R. Neurodegenerative disorders. BMJ 2001;323:879-880 ( 20 October ). 2) Stagnaro S., Valutazione percusso- ascoltatoria della microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e Acta Med.Medit. 145, 163 1986. 3) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: la manovra di Ferrero- Marigo nella diagnosi clinica della iperinsulinemia- insulinoresistenza. Acta Med. Medit. 13, 125 1997. 4 Stagnaro S., Stagnaro-Neri M., Valutazione percusso - ascoltatoria degli attacchi ischemici transitori e della insufficienza cerebrovascolare cronica in pazienti trattati con mesoglicano. Atti, IX Congr. Naz. It. Patologia Vascolare. Copanello, 6-9 Gennaio 1987. A cura di R. Del Guercio, G. Leonardo e G. Zanini. Pg. 765, Monduzzi Ed. Bologna 1987. 5) Stagnaro S., Stagnaro-Neri M., Il Test dell’Apnea nella Valutazione della Microcircolazione cerebrale in Cefalalgici. Atti, Congr. Naz. Soc. Ita. Microangiologia e Microcircolazione. A cura di C. Allegra. Pg. 457, Roma 10-13 Settembre 1987. Monduzzi Ed. Bologna 1987 6) Hoyer S. Models of Alzheimer’s disease: cellular and molecular aspects. Journal of Neurotrasmission.(Suppl.) 49, 11, 1997. 7) Baringai M. Is Apoptosis Key in Alzheimer’s Disease? Science. 281, 1301, 28 August 1998 8) Koudinov A.R., Koudinova N.R.Brain cholesterol pathology is the cause of alzheimer’s disease. Clin. Med. & Health Research, November, 2001.

Behind tau and amyloid beta in AD's pathogenesis. 11 January 2002
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Sergio Stagnaro,
Specialist in Blood, Gastrointestinal, and Metabolic Diseases.
Researcher in Biophysical Semeiotics, Member NYAS and AAAS.

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Re: Behind tau and amyloid beta in AD's pathogenesis.

dottsergio{at}libero.it Sergio Stagnaro

Dear colleagues.

First, I thank the authors very much for have been writing to me, asking my opinion, really modest, about their intriguing research. As many colleagues know, I described formerly a "clinical" method, useful and reliable in recognizing AD even in initial and asymptomatic stage

(See: Alzheimer's disease: the primary role of both insulin and cerebral insulin-receptors responce. Stagnaro Sergio (BMJ.com,16 June 2001), Piazzetta (via Google) and my site: http://digilander.iol.it/semeioticabiofisica). I appreciate their work about AD pathogenesis, at least, because the results of their reaserch, "finally", let me understand and mainly comprehend,from the pathophysiological view-point, my bed-side observations in AD, even in intial,symptomless stage. In fact, their interesting result "imply the link between neuronal lipid metabolism and tau and amyloid beta neurochemistry and propose that the classical AD brain lesions are functional consequences of the neuronal cholesterol and possibly phospholipid biological misregulation". As a matter of fact, my results,showing the characteristic absence of insulin-receptors activity in the brain exclusively in AD patients, even in first, silent stage, demonstrate a neuron as well as synaptic behavioral impairment,induced perhaps by cholesterol metabolism derangement at membrane level. In NO OTHER brain disorder I observed such altered microvascular cerebral response to the acute pick of insulin secretion. My answer gives to their research, perhaps, scarse data to support your really interesting and intriguing theory, which,however, enlightens my clinical data. Therefore, I THANK my dear colleagues with great pleasure. Obviously they are allowed to utilize, as they like, my papers,including the attachement. Yours sincerely.

Stagnaro Sergio MD, Member NYAS and AAAS Riva Trigoso (Genoa) Italy Via E. Piaggio 23/8 16037


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