oops! forgot the enclosures I promised. here they are. Wendy <<<<<< Attached TEXT file follows >>>>>> Content-Type: text/plain; charset="us-ascii" I'm forwarding some research you might enjoy reading. Fletcher --========================_7573406==_ Content-Type: text/plain; name="Alzheimer's_ppr,_part_1"; charset="us-ascii" Content-Disposition: attachment; filename="Alzheimer's_ppr,_part_1" I wrote this paper for my dad, who may have Alzheimer's Disease. It is the result of about 100 hrs work on medline and at the biomedical library. Alzheimer's is in many ways accelerated aging of specific neurons in the brain. In doing research on this paper, I've modified my own anti- aging strategy, most notably by adding Deprenyl, magnesium, selenium, Coenzyme Q-10, DHEA, and pregnenolone (at the appropriate ages). I think most readers of this newsgroup will find this paper interesting. If a doctor says that there's no treatment for Alzhiemer's, the medical literature proves him wrong. It's divided into 3 parts. Any feedback would be appreciated. Alzheimer's Disease: A Treatment Strategy by James L. Rice, 12 December, 1994 Introduction Alzheimer's Disease (AD) is a neurodegenerative disorder of the central nervous system that affects almost 1 in 10 individuals who survive beyond age 65. The disease afflicts 19% of individuals 75 to 85 years old, and 45% of individuals over 85. It is characterized by cerebral cortical atrophy, neuronal loss, neurofibrillary tangles, and neuritic plaques. The primary neuropharmacologic defect involves reduced activity of the enzyme choline acetyltransferase, causing reduced synthesis of acetylcholine (ACh). Other neurotransmitters known to be deficient in AD include dopamine and serotonin. Initially, components of short-term memory and immediate recall are lost, plus a decline in other higher cognitive functions such as attention. Eventually, memory loss is so severe that patients lose the ability to care for themselves. Why Not Tacrine/Cognex? One pharmacologic approach to enhancing cholinergic function involves inhibiting ACh degradation by inhibiting acetylcholinesterase (physostigmine, tacrine). Results of studies involving this approach are conflicting: no consistent benefit has been shown in patients with AD. Although therapy with tacrine has been beneficial in some patients, it has not been effective in all cases and has the potential to cause serious adverse effects. "(With tacrine), the magnitude of the changes (in patients receiving tacrine) was small, even in responsive patients, and many patients responded only partially or not at all. Furthermore, it appears that treatment response is obtained only at higher doses on the margin of patient tolerability." (1) Tacrine appears to have marginal benefit and major side effects "43% of tacrine treated patients had increases in serum hepatic enzyme activity and 51% of tacrine treated patients had adverse events related to treatment." (1) Tacrine is the only drug approved by the FDA for use against AD. An Alzheimer's Disease Strategy A strategy against AD will, of necessity, involve elements not specifically approved by the FDA for AD, but which have either direct evidence of efficacy or a compelling rationalle for their effectiveness combined with little or no risk. In fact, most of the elements in this strategy have numerous benefits including anti- arteriosclerotic effects (slows or prevents heart disease), oncostatic and anti-neoplastic effects (helps fight and prevent cancer), immunostimulatory effects (fights disease), and possibly even extended average and maximal lifespans. The cause of AD is unknown, but there is a large and rapidly increasing number of studies indicating an inflammation response, either due to local insult or genetic mutation may be one source of the damaging processes. My anti-Alzheimer's strategy is multifaceted. Two or more compounds that operate by different mechanisms are likely to prove more effective than any single agent administered alone. The strategy is: I) Accurate diagnosis using the new eye test. (2, 3) II) Drugs or compounds shown to have beneficial effects on AD with few if any adverse effects (Deprenyl, Acetyl-L-Carnitine). III) Replacement of hormones known to be deficient in AD patients (or the elderly in general) to a level found in healthy young adults (DHEA, Melatonin, Pregnenolone), and which have generalized geroprotective or antiaging effects plus indications of efficacy against specific AD etiology. Since AD is a disease of aging, a general anti-aging, or geroprotective, strategy may prove beneficial. IV) Antioxidants (Deprenyl, Melatonin, Magnesium, generalized vitamin therapy). V) Anti-inflammatory Therapy: Drugs and Oral Tolerization I. Diagnosis Diagnosis of AD has been notoriously difficult, and it is frequently misdiagnosed. I suggest replicating the recently reported test for AD involving the ability of a highly dilute solution of the cholinergic antagonist, tropicamide, to dilate pupils in probable AD patients. The general principle of the test is that in AD, acetylcholine-producing neurons degenerate. The dilating compound tropicamide works by interfering with acetylcholine. Presumably, AD patient's eye nerve cells produce very little acetylcholine, so much less tropicamide is required to affect them. Because this test has not yet been translated into a simplified clinical test, it is important to replicate the actual experiment as closely as possible so that results can be compared directly with the experimental data. (2, 3) Procedure: 1) Call an opthalmologist affiliated with a hospital (a hospital will have the ability to prepare the dilute eye drops in a sterile environment- a pharmicist will not), and explain that you want to replicate as closely as possible the procedure described in the article: "A Potential Noninvasive Neurobiological Test for Alzheimer's Disease", Science: Vol 266, 11 Nov 1994, pp. 1051-1053 (3) Tell the ophalmologist that you will need a specially compounded formulation of tropicamide, diluted to 0.01% (normal dilution is 0.5% to 1.0%), prepared prior to your arrival for your appointment, and that you will want the patient's pupil diameter measured at intervals for one hour after administration. Reading the experiment report and getting familiar with the data recording sheets will take some time. Tell them to allow about an hour and a half for the appointment. 2) Take a copy of the experiment write-up in with you, or send a copy to the opthalmologist beforehand. Take the included graph, and blank data table with you. 3) Actual Procedure: A) Have the patient sit in a semidarkened room for 2 or 3 minutes. Measure the resting pupil diameter for 1 minute. Record the average value on the data sheet. Then administer one drop of the dilute solution of tropicamide to one eye. Note the time. Begin timing from this point. B) Examine the eye for pupil diameter for 30 seconds at the following times after drop administration and record the average value of pupil diameter on the data sheet. Times: 2, 8, 15, 22, 29, 41, and 51 min after drop administration. C) Perform the calculations indicated on the data sheet to convert raw pupil diameter measurements to percentage changes from the baseline, or initial measurement. D) Plot the percentage changes at the measurement times on the included graph. Compare the profile with the already plotted profiles of Alzheimer's patients and healthy controls. Which profile more closely matches the patients profile? E) If the profile does not indicate Alzheimer's Disease, then consider the possibility of non-Alzheimer's dementia, such as Korsakoff's syndrome, multi-infarct demetia, and dementia with an extrapyramidal syndrome, and get a doctor's advice on diagnosing and treating the problem. If the profile more closely matches the AD patient's profile, then proceed with the course of treatment indicated herein, in consultation with a physician. II. Drugs or compounds shown to have beneficial effects on AD with few if any adverse effects. Deprenyl (Selegiline, Eldepryl) (-)deprenyl is a drug with a unique pharmacological spectrum. It is a highly potent and selective inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain, whose activity increases significantly with age. One of the monoamines oxidised by MAO-B is dopamine. An inhibitor of MAO-B should, then, increase the dopamine content of the brain. AD is characterized by death of dopamine-producing neurons. It is the only safe MAO inhibitor which can be administered without dietary restrictions. Additionally, maintenance on deprenyl enhances selectively production of superoxide dismutase (SOD). A highly potent enzyme antioxidant, SOD promotes catalase activities in the striatum, and facilitates the activity of the nigrostriatal dopaminergic neurons (the most rapidly aging neurons in the human brain) with remarkable selectivity. It prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substance nigra. (18) Male rats maintained on deprenyl lived longer (198 weeks average vs. 147 weeks for controls in one trial- a 35% increase in average lifespan; in another trial, average survival time increased from 115 to 134 weeks[18]) and showed improved performance in learning tests (rats treated with deprenyl improved 400% in a specific test administered over one year, while the control rats performance declined 12%). Patients with Parkinson's disease given deprenyl chronically from diagnosis required levodopa on average 550 days after diagnosis. Patients not given deprenyl required levodopa in 320 days. Patients with Parkinson's disease maintained on levodopa (a dopamine precursor) and deprenyl (10 mg daily) live significantly longer than those on levodopa alone. Continuous administration of deprenyl improves the performance of patients with AD (4,5). "Deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance on deprenyl improves significantly the performance of patients with AD. It is concluded that Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg deprenyl from diagnosis until death, irrespective of other medication." (6) "It is hoped that the conspicuous harmony between animal and human data will give convincing ground for the proposal that the maintenance on small doses of (-)deprenyl (10-15 mg weekly) from the age of 45 years is reasonable and that continuous (- )deprenyl (10 mg daily) in Parkinson's and Alzheimer's Disease is, irrespective of other therapies, not only justified, but definitely mandatory." (6) "The nigrostriatal dopaminergic neurons which contain 80% of all dopamine are the most rapidly aging neurons in the human brain. The dopamine content of the human caudate nucleus decreases enormously after age 45 by about 13% per decade. Symptoms of Parkinson's disease appear if the dopamine content of the caudate nucleus is less than 30% of the youthful level. Thus, the aging of the striatal dopaminergic system is nromally slow enough to avoid the appearance of such symptoms within the average lifespan. In 0.1% of the population, however, the system deteriorates fast enough to cross the critical threshold while the patient is still alive, and the symptoms of "shaking palsey" are precipitated. MAO contributes to this decline in dopamine by catalysing destructive reactions (oxidative deamination and O-methylation). Also, when dopamine oxidises, it produces substantial quantities of toxic free radicals and highly reactive quinones, which then attack the nigrostriatal dopaminergic neurons. The waste products of these reactions are thought to be what makes up the "age pigment", or lipofuscin, which accumulates in the brain with age, and which may interfere with it's functioning. The organism survives in the face of these attacks only by the ability of superoxide dismutase (SOD) to counteract the free radicals. Deprenyl enhances the production of SOD in the striatum of rats." (6) Regarding cognitive enhancers, of which deprenyl is one, "A review of the literature points out that the day-after approach of treatment (once severe neuropathological damage has been established) is no longer feasable, or has limited advantages. A different pharmacological approach, based on preventive measures during the first stages of theneurodegeneration, seems mandatory." (7) "Regarding the consequences of the protecting effect of deprenyl in healthy humans against the age related decline of the striatal dopaminergic system, it is worth considering that just a small change in the rate of decline, e.g. from 13% per decade to 10% per decade, anticipates at least a 15-year extension in average lifespan and a considerable increase of the human maximum possible lifespan, which is now estimated to be 115-120 years, to 145 years. Preventive deprenyl medication may also retard the precipitation of Parkinson's and Alzheimer's diseases in the endangered population." (6) "The beneficial effect of prolonged treatment with deprenyl on learning and retention in selected low performer rats is in accordance with the rapidly growing unequivocal clinical evidence that the administration of deprenyl improves the performance of Alzhiemer's patients significantly. The pharmacological profile and the safety of deprenyl allowed the conclusion that in Parkinson's disease and Alzheimer's disease 10 mg of deprenyl daily should be administered from diagnosis until death, independent of any other kind of medication." (8) Side effects of Deprenyl may include elevated dopaminergic symptoms and elevated liver function enzymes. However, the risk of serious hepatic toxicity is little or none. Other reported side effects include nausea (14%), dizziness(12%), abdominal pain(4%). None of the side effects were bad enough that treatment was discontinued. (9) Deprenyl (5 mg) should be taken with breakfast and lunch to avoid reported insomnia with evening dosing. (10) "Selegiline (Deprenyl) seems to be safe in combination with low- dose tacrine and it may reduce the dose of tacrine needed for a positive treatment response in AD." (11) "16 out of 18 available reports of clinical studies (including pen, comparison, and double-blind, placebo-controlled designs) with a total of approximately 790 AD patients, with 450 treated on selegiline from one to 12 months, indicate that selegiline in addition to providing a potential symptomatic therapeutic efficacy, may retard the progression of AD." (12) I therefore suggest 10 mg of deprenyl be taken daily (5 mg with breakfast, 5 mg with lunch) for any Alzheimer's patient. Acetyl-L-Carnitine "Acetyl-L-Carnitine (ALC) is the acetyl ester of carnitine, a naturally occurring substance that acts as a carrier of fatty acids from the cytosol into the mitochondrial matrix where they can be subjected to B-oxidation. ALC is freely exchanged across membranes and can provide acetyl groups from which to regenerate acetyl-CoA, therefore facilitating the transport of metabolic energy. ALC, unlike L-carnitine, easily enters the brain. Experimental studies have demonstrated that ALC promotes Acetylcholine synthesis and release." (13) "Defects in cholinergic neurotransmission do not, by themselves, constitute the sole pathophysiologic concomitants of AD. Recent findings point out that abnormalities in membrane phospholipid turnover and in brain energy metabolism may also characterize AD. ALC is an endogenous substance that, acting as an energy carrier at the mitochondrial level, controls the availability of acetyl-L-CoA. ALC has a variety of pharmacologic properties that exhibit restorative or even protective actions against aging processes and neurodegeneration. A review of a series of controlled clinical studies suggests that ALC may also slow the natural course of AD." (13) "In open studies, ALC has been administered to patients affected by cognitive impairment or true AD. ALC proved to be safe and well tolerated, inducing only minor and transient side effects (agitation, gastric upset). Therefore, a series of double-blind, placebo-controlled trials have been performed for better defining ALC's efficacy in patients with AD." (13) In nine trials from 1985 to 1990, where daily doses of ALC from 1 to 3 grams were administered, very good efficacy was obtained in four of the studies, good efficacy was obtained in one, some efficacy was obtained in two, and a mild negative efficacy was obtained in one. (13) Generally, ALC slowed but did not stop the deterioration in cognitive function. "Although further insights into the mechanisms underlying the ALC effect are needed as are additional controlled trials on a larger number of AD patients (currently in progress), we believe that preclinical and clinical evidence supports the hypothesis that ALC has therapeutic impact on the progression of AD." (13) "There were no major adverse side effects associated with administration of Acetyl-L-Carnitine." (14) "Treatment with L-carnitine, a manipulation designed to mitigate consequences of a mitochondrial abnormality, normalized several non-mitochondrial abnormalities in cultured Alzheimers cells." (15) I therefore suggest the consumption of 2 grams of Acetyl-L- Carnitine daily in three divided doses by AD patients. III. Generalized Antioxidant Therapy "Reactive oxygen metabolites (ROM), namely superoxide and hydroxyl free radicals and hydrogen peroxide, are produced as a consequence of the physiological metabolic reactions and functioning of the central nervous system. ROM have also been implicated in the aetiopathogenic processis of a number of pathological conditions of the brain. While primarily indirect, evidence for this view is accumulating, and credence for the participation of free radical oxidative interactions in promoting tissue injury in such conditions as brain trauma, ischaemia, and toxicity, and in neurodegenerative diseases such as Parkinson's, Alzheimer's dementia, multiple sclerosis, and lipofuscinosis, is growing. Concomitant with this new understanding of the injurious role of free radical oxidants in neural pathology, is the increasing appreciation of the need for both fundamental and clinical research into the development of the potential preventative and therapeutic benefits that are now being foreseen for a variety of antioxidant nutritional and pharmacologic interventions." (16) "Compelling evidence suggests that cerebral deposition of aggregating B-amyloid protein may trigger the neurodegenerative cascades of AD, down syndrome, and, to a lesser degree, normal aging. We propose further that free oxygen radicals are critically involved in B-amyloidosis. Apart from the established role of free radicals in other amyloidoses, this is consistent with a large number of findings: a) the salient relationship of AD with aging and the increase in free oxygen radical liberation with advancing age; b) biochemical and analytic epidemiologic evidence that free radical formation is increased in the disorder; c) preliminary evidence that quenching free radicals slows the clinical progression of AD; d) the early and invariable B-amyloid accumulation in trisomy 21, a syndrome associated with elevated free radical activity and with concommittent high levels of B- amyloid precursor protein." (17) "Some direct evidence indicates that free radical activity may be increased in AD. Numerous abnormalities in AD such as condensed chromatin and increased membrane permeability are consistent with the free radical hypothesis. Vitamin E has been reported in two studies to be depleted in AD. A primary role for free oxygen radicals in AD implies that quenching free radicals would provide an effective treatment strategy, an extrapolation that is not without empirical support. Desferrioxamine is an iron chelator that does not cross the blood-brain barrier and is known to attenuate iron catalyzed radical formation. It has been reported that in the first clinical trial of desferrioxamine mesylate in AD that the chelating agent may retard the clinical progression of AD. Additionally, deprenyl, a MAO-B inhibitor that has antioxidant properties, has been reported to decelerate the rate of cognitive impairment in AD." (17) "Initial studies using high dose nutritional antioxidant vitamins E and C and the monoamine oxidase inhibitor Deprenyl, have culminated in a large scale multicentre controlled trial with deprenyl and vitamin E which demonstrated the efficacy of the drug regime in reducing the rate of progression if Parkinson's disease." (16) "Indirect evidence indicating an enhancement of oxidative stress in AD stems from studies showing increased levels of brain glucose 6-phosphate dehydrogenase and red cell glutathione peroxidase activities, elevated susceptibility to membrane lipid peroxidation, and reduced plasma levels of the antioxidant micronutrients vitamins A and E, and carotenoids....The capacity of vitamin E to protect cultured nerve cells against the cytotoxic effect of the B- amyloid protein associated with AD has significant therapeutic implications... The in vitro induction of Alzhiemer-type paired helical filaments following addition of oxidative phosphorylation uncoupling agents to normal fibroblast cells, and the addition of glutamate to human neurones, illustrates a potential oxidative pathogenic mechanism. A recent report of enhanced susceptability of Alzheimer skin fibroblasts to ROM-mediated damage, provides pertinent new evidence of a compromised antioxidant defence system in AD." (16) "Lipofuscin, or age pigment, has been shown to accumulate in human brains with age, with further increases occuring in AD. The importance of oxidant-mediated processes in lipofuscin formation has been demonstrated using in vitro culture studies of human glial cells, showing that prooxidants (ex.- iron) accelerate, while antioxidants (vitamin E, selenium, and GSH) reduce lipofuscin levels." (16) "Clinical investigations in elderly humans using nutritional supplements of various mixtures of vitamins E, C, and selenium has provided some encouraging results. The potential of nutritional and dietary modulation of ROM-related tissue injury offers the general attraction of a population-based, early, long term and minimally-hazardous intervention for the prevention of neurodegenerative damage. It has been calculated that a postponement of 5 years in the onset of AD could reduce morbidity by half." (16) "Cholinergic neurotransmission is known to be exquisitely sensitive to conditions that impair oxidative metabolism and neuronal membrane function." (18) Vitamin E reduces the hepatotoxicity of tacrine, and so should be considered a necessary adjunct to tacrine therapy. (19, 20) A therapy of iron (50-150mg), vitamin B-6 (90-180mg), and Coenzyme Q10 (60-180mg) on 20 AD patients over a period of one year showed stabilized disease and improved scores on the Mini Mental Status Exam. MMSE scores at the start of treatment were 14.5+-7.0; at the end of one year 21.6+-6.5. The logic of treatment was that iron, while normally an oxidant and free radical generator, is nonetheless important to brain function. Coenzyme Q10 has antioxidant capabilities and stabilizes cell membranes, especially mitochondrial membranes. CoQ10 may have neutralized the iron-derived free radicals. Vitamin B6 is used in the biosynthesis of GABA (gamma-aminobutyric acid). Glutamine induced neurotoxicity is postulated to be one cause of neuronal cell death. GABA reduces glutathione. Given the known free radical generating properties of iron, and the fact that the iron-chelating drug desferrioxamine has reduced the rate of progression of AD (16), I consider it somewhat unlikely that the iron supplements aided the AD patients. I would therefore omit iron but include Coenzyme Q10 and vitamin B-6 in an AD therapy. (21) There are no known side effects at the recommended dosages for vitamins. Selenium doses should be less than about 500 mcg/day, as some toxic effects have been noted at 1000 mcg/day. No known toxic effects of Coenzyme Q10 are present at recommended dosages. I therefore recommend the AD patient take three times daily with meals at least 400 i.u. of vitamin E, one half gram of vitamin C, 25,000 i.u. of beta carotene (or, even better, consumption of a high dose multivitamin) , and 200 mcg of selenium. .Also take 120 mg Coenzyme Q10, and 120 mg B-6 in three divided doses. I do not recommend taking supplemental iron. Additionally, the patient should try to maximize his/her consumption of fruits and green vegetables, striving for five to six servings a day. Magnesium "Oxidative stress and neurodegenerative processes are accompanied by a pronounced magnesium deficiency. This is also true for diseases associated with premature aging such as Down syndrome." (23) "Magnesium deficiency affects calcium transport and iron sequestration, impairs mitochondrial function, and induces radical generation by redox recycling. In contrast, magnesium administration improves energy and glucose utilization, stablizes enzymes and membranes, and protects biomolecules against oxidative damage by reactive radicals. It has been demonstrated that magnesium exhibits potent chemo- and cardio-protective actions. Newly developed magnesium salts, with greatly enhanced oral bioavailability and exhibiting extremely low toxicity, have been used sucessfully to counteract stress and age-related excitotoxicity in experiments in animals and humans. The administration of magnesium salts with high bioavailability (magnesium chloride [Slo-Mag], magnesium citrate [Citroma], magnesium hydroxide [Mag-Ox], magnesium pidolate) [22]prolongs life span and reverses age-related morphological, biochemical, electrophysiological, and behavioral impairments." (23) "The three major molecular mechanisms that have been identified as being involved in the irreversible process of specific neuronal death during aging are glutamate-mediated excitotoxicity, intra- neuronal calcium overload, and hydroxyl radical-induced peroxidation and oxidative damage to biomolecules." (23) Magnesium affects all of these mechanisms favorably. Magnesium also reverses the age-dependent decline in melatonin production. "The elderly may be at risk of developing a magnesium dificiency due to poor food selection, decreased absorption, diseases that cause magnesium depletion, or medications that may increase urinary loss of magnesium." (22) I therefore suggest consumption of a magnesium salt sufficient to provide 400 -800mg of elemental magnesium per day.. Example: 2 tablets of magnesium chloride (OTC: Slo-Mag) three times a day (6 total/day) with meals. IV Replacement of Hormones Known to be Deficient in AD Patients Melatonin. Melatonin is a hormone produced at night in the pineal gland. It is associated with sleep and circadian rhythm. It is a very potent and efficient endogenous radical scavenger. It reacts with the highly toxic hydroxyl radical and provides on-site protection against oxidative damage to biomolecules within every cellular compartment. Melatonin production declines in a very regular and predictable way with age. While in young animals and humans the 24-hr cycle of melatonin is very robust, the cycle frequently deteriorates during aging and is totally abolished in neurodegenerative diseases such as Alzheimer's Disease (23,). Agents that are active against the symptoms and progressions of diseases associated with accumulating oxidative damage and neuronal degeneration, such as acetyl-L-carnitine and magnesium, prevent the age-associated decline in nocturnal pineal and blood melatonin in rodents. (32) The exogenous administration of melatonin substantially extends the life span in experimental animals (32). Melatonin exerts direct and indirect beneficial effects in delaying developmental and aging processes. (28,32) "The diurnal rhythm of melatonin can be substantially perserved during aging by restriction of food intake or other nutritional and pharmaceutical treatments in rodents; these treatments increase life span and prevent premature aging as well as delay the onset of neurodegenerative diseases." (33) Melatonin has antagonistic effects on glutamate-mediated excitotoxicity, one of the three mechanisms proposed for neuron death during aging. Melatonin is a highly efficient free radical scavenger, especially of hydroxyl, thus counteracting another of these mechanisms, hydroxyl-radical induced peroxidation and oxidative damage to biomolecules. Dementia due to prematureaging in patients with Down syndrome or accelerated aging in patients with Alzheimer's disease may be attributed to an enhanced exposure to hydroxyl radicals. Melatonin is the best known free radical scavenger. Additionally, melatonin reportedly exerts potent oncostatic, immunostimulatory, and rejuvenating effects in old rodents. (22) "Several lines of evidence suggest that abnormalities in oxidative metabolism and specifically in mitochondria may play an important role in Alzheimer's disease. The abnormalities include a profound deficit in the activity of the ketoglutamate dehydrogenase complex (KGDHC), which is likely to lead to impaired metabolism of glutamate and might contribute to selective neuronal cell death by excitotoxic mechanisms." (15) "The plasma half-life of melatonin is relatively short. Plasma profiles produced by oral formulations are markedly dissimilar to the typical in vivo plasma profile. In healthy young subjects, melatonin can be detected for 10-14 hr per night at a level that typically varies between 100-300 fm/ml. In contrast, bolus oral and i.v. doses typically produce pharmacological levels (in the nanomolar range) that are excreted within 2-5 hr." (34) "The difference between the endogenous profile and that produced by exogenous administration may be of critical importance. Many of the physiological effects of melatonin in animals appear to be related to the duration of the plasma profile rather than the plasma level per se. If melatonin is to be developed as a successful clinical treatment, differences between the pharmacological profile following exogenous administration and the normal endogenous rhythm should be minimized. Continued development as a useful clinical tool requires control of both the amplitude and duration of the exogenous melatonin pulse. There is a need to develop novel drug delivery systems that can reliably produce a square-wave pulse of melatonin at physiological levels for 8-10 hr duration." (34) Since there is not now available a commercial timed-release formulation of melatonin, (it should be available relatively soon), imitating the natural youthful physiologic profile should be attempted by doing two things: Take a large initial dose (say, 6-10 mg) right before bed. Melatonin will remain in the blood longer. And, if the patient wakes up in the middle of the night with at least 4 hours of sleep left, he/she should take another 3 mg capsule of melatonin. At extremely high doses (200 mg/day and above), melatonin increases depression and insomnia. At doses of around 3-30 mg/day, no known side effects are evident, other than the hypnotic effect (sleepiness). (34) Melatonin should not be taken by patients with myelocytic leukemia or multiple myeloma. Melatonin production is supressed by vitamin B12 supplementation, a supplement frequently taken by the elderly to avoid pernicious anemia. I therefore suggest nightly consumption of 6 to 10 mg melatonin just before going to sleep, and consumption of an additional 3 mg if the patient wakes up in the night with at least 4 hours of sleep to go. When timed-release melatonin becomes available, I suggest using that. Dehydroepiandrosterone (DHEA) Dehydroepiandrosterone (DHEA) is a hormone of the adrenal cortex. It peaks at around 20 to 30 years of age at 50 to 100 ug/dl, and declines thereafter at about 20% every decade after age 25, stabilizing at 5% of youthful levels at age 85. Administration of DHEA or certain analogs produces an array of beneficial effects on obesity, muscle strength and mass, type II diabetes, cholesterol levels, autoimmunity, cancer initiation and proliferation, osteoporosis, memory, and aging. It has been reported that an increase in plasma DHEA is correlated with a 36% reduction in mortality from all causes, and a 48% reduction in mortality from cardiovascular disease. (35, 43) "(It has been suggested) that acetylcholine (Ach) neurotransmitter activity manifests its physiologic action through inhibition of K+ channels in the cell membrane which serves to maintain neuroexcitatory activity. Based on this, Roberts postulated that the progressive debilitation of aging, as is seen in AD, could be due to gradual decrease in 'the capability for genetic transcription of major K+ channel components so that the ability of cells to adjust to changing conditions would be lost.' He felt that the progressive decline in the hormonal DHEA, DHEA-S levels with advancing age may be a key factor producing the debility of aging leading to AD through loss of K+ channel inhibition. The postulate that DHEA would inhibit K+ channels was based on DHEA's broad physiologic action: modulation of diabetes, tumor induction, and effects on autoimmune response which Roberts felt were key factors in preventing age-related events. Regardless of the validity of his concept, he has found that DHEA and it's sulfate in tissue culture enhanced neuron and glial survival...Robert's concept may be further supported by the high concentration of DHEA-S found in the brain (6.5 times plasma concentrations), which suggests that DHEA may have modulating effects on cell membranes which alter response to neurotransmitters." (35) DHEA and it's sulphonated metabolite DHEAS are the major secretory product of the human adrenal gland. "Reduced plasma levels of DHEA (48% less than age matched controls) have been found in AD patients. DHEA and DHEA-S enhance memory retention in mice and block the memory impairing effects of scopalomine. Besides anti-amnestic effects, DHEA-S may protect partly degenerated or at-risk brain cells." (42) "DHEA has been likened to an "antihormone", which cannot serve to excite in the true classical sense of hormone action, but deexcites metabolic processes which overproduce when DHEA is in short supply. DHEA may act by buffering or antagonizing the action of corticosteroids to modify stress-mediated injury to tissue, an action which may be critical to the diseases of aging." (43) "DHEA-S was shown to block enzymatic effects of glucocorticoids, thus, a certain part in the progression of AD may be played by the decrease in DHEA-S and its antiglucocorticoid functions." (36) "In a study of 24 AD patients and 50 controls, subjects were examined for DHEA-S/cortisol ratios. A strong negative correlation was found between age and DHEA-S, but no significant correlation was found between cortisol levels and age; therefore, the DHEA-S/cortisol ratio dropped remarkably in older normal subjects as compared to young individuals. Interestingly, a trend was found for a lower DHEA-S/cortisol ratio in AD patients compared to age- and sex-matched controls. indicating that the ratio could be an appropriate measure for the effects of DHEA-S as an antiglucocorticoid by which subjects at risk for the neurotoxic effects of glucocorticoids could be identified. These previous results suggest a possible relation of cognitive impairment to circulating corticoid levels (37, 43), and they indicate a possible role of DHEA-S in diminishing cortisol effects on hippocampal cells avoiding progressive hippocampal degeneration in AD." (38) "While the nature of possible antiglucocorticoid effects is unknown, several authors have reported physiological antagonism by DHEA of corticosteroid effects such as thymic involution and suppression of lymphocyte proliferation. We propose that, in addition to such "pharmacodynamic" effects, DHEA may have a "pharmacokinetic" effect on circulation cortisol levels. Pharmacologically induced increases in DHEA levels are significantly correlated with decreases in 4 p.m. serum cortisol levels." (39) "Physicians are testing DHEA as a possible therapy for systemic lupus erythematosus, a chronic inflammatory disease. In lupus, the immune system goes awry and makes abnormal antibodies that can damage or sometimes destroy the kidneys, brain, or heart. Experimental evidence that DHEA benefits mice that develop a lupus-like disease, coupled with the observation that DHEA levels are abnormally low in patients with lupus, led researchers to test the hormone in 57 women with lupus. The women took 50-200 mg of oral DHEA every day for 3-12 months. About two- thirdsreported some relief of symptoms including rashes, joint pain, headaches, and fatigue. 'DHEA has the potential to be an important drug in lupus, particularly because of its apparent ability to significantly reduce the need for steroids', said one scientist." (40) Thus, there are indications that DHEA administration is helpful in mitigating an autoimmune inflammatory response. AD has now been shown to have autoimmune inflammatory etiology. DHEA's anti-inflammatory effect could, therefore, be therapeutic for AD. Large-scale clinical studies are now underway of DHEA and AD patients at the National Institute of Mental Health. (41) Cognitive impairment due to endogenous hypercortisolemia may be prevented by anticorticoid hormonal treatment. (37) Chronic glucocorticoid administration leads to hippocampal damage in the rat and, due to a dysfunction of the hypothalmic-pituitary-adrenal axis, to progressive dementia. (36) "Based on animal studies, the anticipated potential benefits of DHEA replacement therapy would be: (a) increased mitochondrial respiration of the liver, (b) increased fatty acid deacylation, (c) reduced blood serum cholesterol, (d) reduced LDL cholesterol, (e) increased memory retention, (f) increases in calcium deposition and bone density, (g) increased muscle mass and strength, (h) increased skin thickness, (i) stimulation of the immune system as measured by an antiviral and antibacterial action, (j) reduced shrinkage of the thymus gland, (k) chemo-preventative activity for certain cancers (breast and colon) (l) decreased blood pressure, (m) anti-obesity action by reducing blood sugar and insulin, (n) reduced negative effects of stress, and (o) increased sex drive and performance." (42) "Possible side effects, based on animal studies at extremely high doses, are: (a) male pattern baldness, (b) hirstutism, (c) pituitary tumors, (d) liver hypertrophy, and (e) prostate hypertrophy. It is not likely that doses needed to give a blood level equivalent to a 25 year old would cause any problem. With proper physiological monitoring, the potential benefits may greatly outweigh any potential risks for many people." (42) There have been suggestions that since DHEA has an androgenic role, it might exacerbate prostate cancer, and thus tests to ensure the absence of prostate cancer were recommended proir to starting a DHEA replacement program for men. Recent studies show no effect on prostate growth (35), and DHEA had no proliferative effect on transplanted prostatic cancer cells in mice. (46) Prostate cancer tests prior to DHEA replacement are therefore probably unnecessary (they may be valuable in their own right, however).In fact, given the oncostatic and anti-neoplastic properties of DHEA, DHEA may actually help prevent and fight prostatic cancer. I therefore suggest daily hormone replacement therapy with DHEA (one capsule in the morning) to achieve youthful DHEA levels for Alzheimer's patients. Guidelines: It is important to use antioxidants with DHEA because of the possibility of oxidative stress on the liver. Uptake of DHEA varies from person to person. Because of that, testing at intervals is important to ensure proper levels of DHEA are being achieved. Step One: Get a DHEA-Sulfate blood test. A doctor must order this test. Analyze the results compared to a normal 25 year old's serum levels. Average DHEAS levels in young men are 9.2 umol/litre. Average levels for young women are 7.1 umol/litre. Average levels for both sexes age 85 and older are 1.7 umol/litre. (30) If you take too much DHEA, there could be an inhibition of the adrenal glands to produce any DHEA. Assuming you are deficient as shown by the test, initiate your DHEA intake at doctor-recommended levels. Note: given average DHEAS levels in young and old people and the standard deviation around those levels, a dose of 200-250 mg DHEA/day would be very unlikely to be excessive if you are over 70 years of age, even without an initial test for DHEAS levels. Step Two: After using DHEA for two months, obtain another DHEAS test. Have your blood drawn at least 3 hours after your normal morning dose of DHEA, and at the same time of the day as your first test (DHEA secretion varies during the day according to your circadian rhythm. Adjust your dose, if necessary. Pregnenolone "An additional approach (to ameliorating corticosteroid-associated behavioral and cognitive impairment in certain patients), involving the administration of precursor steroid hormones, has been recently proposed. The biosynthesis of steroid hormones begins with cholesterol, from which the glucocorticoids, mineralcorticoids, and sex steroids all derive. Pregnenolone, a key cholesterol metabolite, is the major precursor for the steroid hormones. Its formation, regulated by pituitary hormones, may become rate-limiting in aging, stress, and other conditions, resulting in steroid imbalances. The recent findings of a striking memory-enhancing effect of pregnenolone and literature showing virtually no human toxicity, suggest that administration of pregnenolone may help reestablish normal relations among the various steroids when abnormalities occur." (39) >From the Geriatric Research Education and Clinical Center, Veterans Administration Medical Center, St. Louis, MO: "Immediate post-training intracerebroventricular administration to male mice of pregnenolone (P), pregnenolone sulfate (PS), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, dihydrotestosterone, or aldosterone caused improvement of retention for footshock active avoidance training, while estrone, estradiol, progesterone, or 16 beta-bromoepiandrosterone did not. Dose-response curves were obtained for P, PS, DHEA, and testosterone. P and PS were the most potent, PS showing significant effects at 3.5 fmol per mouse. The active steroids did not show discernible structural features or known membrane or biochemical effects that correlated with their memory-enhancing capacity. The above, together with the findings that DHEA acted even when given at 1 hr after training and that P, PS, and DHEA improved retention over a much wider dose range than do excitatory memory enhancers, led to the suggestion that the effects of the active steroids converge at the facilitation of transcription of immediate-early genes. P and PS, for which receptors have not yet been demonstrated, may exert their effects by serving as precursors for the formation of a panoply of different steroids, ensuring near-optimal modulation of transcription of immediate-early genes required for achieving the plastic changes of memory processes. Low serum levels of P in aging and the increases of cancer and behavioral disorders in individuals receiving drugs that block synthesis of cholesterol, the immediate precursor of P, suggest possible clinical utility for P." (47) I therefore suggest pregnenolone supplementation (30mg/day initially) for Alzheimer's patients. Typical dosages vary from 10 to 100mg/day. V. Anti-Inflammatory Therapy: Drugs and Oral Tolerance "The etiology of AD is unknown. Recent evidence has demonstrated that activation of inflammatory and immune mechanisms accompanies the degenerative process in the disorder...In AD, physical examination does not indicate inflammation, but more sensitive serologic and tissue studies do provide evidence of inflammatory activity....These results indicate that a process, perhaps the degeneration of brain tissue, is stimulating an acute phase response in AD...The acute pahse response, whether systemic or local, may thus be important in elevating levels of amyloid precursor protein and creating a proteolytic environment favoring the production of amyloid B protein, a component of amyloid placques associated with the disease." (48) "What initiates the pathogenic mechanisms in AD?...If there is impairment of the blood-brain barrier, previously protected brain antigens, or altered antigens, may be exposed to the immune system. Inflammatory and immune mechanisms may thus be initiated (and may be self-propagating), leading to tissue destruction in the brain. Once inflammatory mechanisms are active in brain tissue, they may contribute to disruption of the blood-brain barrier." (48) "Monozygotic twins show discordant expression of AD, indicating the importance of nongenetic factors; variation in inflammatory response may be one such factor. However, unaffected first-degree relatives of patients with AD have elevated levels of acute phase reactants in the serum, in addition to a 50% chance of contracting the disease; the the mean reactant values are intermediate between those of normal subjects and those of AD patients. If acute phase reactants are elevated in a population at high risk but clinically unaffected, the inflammatory response in AD may not be solely a reaction to tissue destruction. On the basis of the preceding mechanisms, supression of the acute phase response and inhibition of accumulation and activation of macrophages are potentially therapeutic and pharmacologically feasable." (48) "It is abundantly clear from papers submitted to this Forum (45th Forum in Immunology, 1992) that elements of the immune system are involved in the pathogenesis of the principle lesions characterizing AD. While the full spectrum encompassing typical events involved in the classical inflammatory response is not yet evident, present findings are in accord with features associated with both the innate and adaptive immune mechanisms." (49) "It appears that a prolonged exposure to the non-degradable but potentially toxic amyloid substance may initiate an immune reaction and cause cell injury that may provoke inflammatory responses." (49) "The bulk of the evidence presented points to the operation of a chronic inflammatory response which may begin insidiously as a "low grade smoldering response" that does not resemble acute inflammation. The evidence indicates tthat the inflammatory response is produced locally within the parenchyma; however, it also seems to entail communication with the circulation. Remarkably, the brain holds the capacity to produce almost all the immune system mediators which largely seem to be generated by glia composing both astrocytes and microglia (representatives of the immune system's monocytes and macrophages, which contribute to inflammatory responses). This fact beacons a fundamental change in our thinking that the brain is not necessarily immunologically privileged as first impressions would indicate, but seems to have its own immune system and can readily mount a full immune attack." (49) "Serum from AD patients contained antibodies that recognized cholinergic neu ronal elements in the adult rat brain, namely the medial septum, hippocampus, and cortex. Another group of investigators showed that AD serum contained antibodies directed against the purely cholinergic Torpedo electromotor neurons. Antibodies directed against microglial cells were present in a much higher frequency in AD cerebrospinal fluid, compared to CSF from other dementia patients." (50) Anti-inflammatory Drugs Corticosteroids. Glucocorticoids are the most broadly active anti- inflammatory/immunosuppressive agents in clinical use. Steroids are the mainstay of treatment for idiopathic inflammatory diseases of the central nervous system. Unfortunately, there are serious drawbacks to clinical trials of this class of drugs in AD. The known systemic toxic effects of moderate to high doses of corticosteroids in humans are numerous. Experiments in animals have demonstrated that prolonged exposure to glucocorticoids is toxic to hippocampal neurons, and impairs the capacity of neurons to survive insults; it is feared that patients with underlying brain disease may be particularly prone to adverse effects of steroids. (48) However, with the use of markers for inflammatory activity, possible beneficial effects of low doses of steroids can be assessed. Chronic administration of prednisone at low doses (i.e., 10 mg/day or less) to elderly patients is well tolerated and effective in the treatment of systemic inflammatory diseases such as rheumatoid arthritis. (48) Nonsteroidal Anti-Inflammatory Drugs (NAID). These drugs are the first line drugs for inflammatory diseases such as rheumatoid arthritis and gout. It has been reported that the prevalence of AD in patients with rheumatoid arthritis is unexpectedly low. Using Canadian and American hospital data covering more than 12,000 patients older than age 64, only 0.39% of those diagnosed with rheumatoid arthritis had also been diagnosed with AD, whereas in the general population the same age group had an AD prevalence of 2.7%. This leads to the hypothesis that medications administered to arthritis patients, such as NAID, confer protection against AD. (51,53) Additionally, a recent study comparing the drug-taking history and likelihood of contracting AD of 50 pairs of elderly twins and found that the twin who had been taking anti- inflammatory drugs had four times greater likelihood of being the later-affected or non-affected member of the pair. Anti- inflammatory drugs used by one of the twins included ibuprofen, piroxicam, naproxen, and some steroids used in the 1950s and 1960s for arthritis but are no longer prescribed. (48,51) Indomethacin. A recent 6-month controlled trial of indomethacin in patients with AD showed stable cognitive function in the the drug-treated group and declining function in the placebo group. The study was small (14 patients in each group completed the study) and there was a relatively high rate of adverse effects from indomethacin's gastrointestinal side effects, which caused the drop-outs in the indomethacin-treated group. The other group lost 20% of the subjects due to decline in behavior to the point that they wouldn't take medicine or sit for the test anymore. That didn't happen with the indomethacin patients (51,52). "100 to 150 mg/day indomethacin appeared to protect mild to moderately impaired Alzheimer's disease patients from the degree of cognitive decline exhibited by a well-matched, placebo-treated group. Over a battery of cognitive tests, indomethacin patients improved 1.3% (+/- 1.8%), whereas placebo patients declined 8.4% (+/- 2.3%)--a significant difference (p < 0.003). Caveats include adverse reactions to indomethacin and the limited scale of the trial." (52, 53) Dapsone. "1991 brought additional evidence in favor of the inflammatory hypothesis from an unexpected source. A local government health official noted what appeared to be an extremely low incidence of dementia in a leper colony on the island of Nagashima. Following up, a study on 4000 aged Japanese leprosy patients was performed. The result: The incidence of dementia wasonly 2.9% in those taking the leprosy drug dapsone, which also has anti-inflammatory effects, but 6.25% among those who has not taken the drug for 5 years. Another group of Japanese researchers analysed the autopsied brains of 16 leprosy patients that had probably been treated with dapsone. They found an unusual abscence of senole plaques in the leprosy patients brains compared to those of age-matched controls. (51) Due to the renal toxicity of Dapsone, I do not recommend it's use, since there are other, much better tolerated anti-inflammatory drugs. Dapsone provides further evidence of the efficacy of anti-inflammatory drugs, however. "The rheumatologist's armamentarium offers a number of other candidates for trials in patients with AD. Potent anti- inflammatory/immunosuppressive agents such as methotrexate, azathioprine, and cyclophosphamide have proven effective in ameliorating the manifestations of lupus, rheumatoid arthritis, polymyositis, and the systemic vasculitides. These drugs have the potential to cause life-threatening toxicity, but with close monitoring, long-term administration may be feasable. Methotrexate may be the best candidate in this group for study in AD. In rheumatoid arthritis, it is highly effective and relatively well tolerated. Its mechanism of action may involve interference with the activity of interleukin-1...Interleukin-1 may be an important mediator of the microglial proliferation in AD" (48) Recommendations There is evidence of AD amelioration with the anti-inflammatory ibuprofen. Although there is no evidence for the specific antiinflammatory aspirin, in view of the above information, if no antiinflammatory drugs are currently being taken by the Alzheimer's patient, I recommend one enteric-coated 325-mg aspirin be taken with breakfast, and one ibuprofen tablet be taken with dinner. If the disease continues to progress with the above therapy, I recommend initial therapy with indomethacin (100-150 mg/day). Due to possible exacerbation of gastric problems, discontinue aspirin and ibuprofen therapy during indomethacin use. If indomethacin cannot be tolerated, then re-initiate aspirin and ibuprofin therapy, and try chronic administration of prednisone at low doses (10 mg/day or less). Commence a search for a nonsteroidal antiinflammatory drug which can be tolerated. Examination of drugs used in rheumatoid arthritis, such as methotrexate, may provide possible candidates. Oral Tolerance "Oral tolerance is a long recognized method to induce peripheral immune tolerance. The primary mechanisms by which orally administered antigen induces tolerance are via the generation of active suppression or clonal anergy. Low doses of orally administered antigen favor active suppression whereas higher doses favor clonal anergy. The regulatory cells that mediate active suppression act via the secretion of suppressive cytokines such as TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore, antigen that stimulates the gut-associated lymphoid tissue preferentially generates a Th2 type response. Because the regulatory cells generated following oral tolerization are triggered in an antigen-specific fashion but suppress in an antigen nonspecific fashion, they mediate bystander suppression when they encounter the fed autoantigen at the target organ. Thus it may not be necessary to identify the target autoantigen to suppress an organ-specific autoimmune disease via oral tolerance; it is necessary only to administer orally a protein capable of inducing regulatory cells that secrete suppressive cytokines. Orally administered autoantigens suppress several experimental autoimmune models in a disease- and antigen-specific fashion; the diseases include experimental autoimmune encephalomyelitis (EAE), uveitis, and myasthenia, collagen- and adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition, orally administered alloantigen suppresses alloreactivity and prolongs graft survival. Initial clinical trials of oral tolerance in multiple sclerosis, rheumatoid arthritis, and uveitis have demonstrated positive clinical effects with no apparent toxicity and decreases in T cell autoreactivity." (55) There is strong evidence that inflammatory processes are involved with AD, via an autoimmune response. This is also the case in rheumatoid arthritis. Antiinflammatory drugs which are used in arthritis also may have efficacy in AD (51-53), indicating a common cause or disease process. Oral tolerization has beneficial effects on arthritis. Therefore, it seems logical to assume that it might be effective against AD. There is evidence that brain tissue of non-human origin is similar enough to human tissue to induce AD patient antibody recognition: "Serum from AD patients contained antibodies that recognized cholinergic neuronal elements in the adult rat brain, namely the medial septum, hippocampus, and cortex. Another group of investigators showed that AD serum contained antibodies directed against the purely cholinergic Torpedo electromotor neurons." (50) Consumption of healthy animal brain tissue is not known to have adverse side effects . Oral consumption of myelin has succeeded in reducing the frequency of Multiple Sclerosis attacks. (56) I therefore recommend daily or weekly consumption of small amounts of healthy animal brain tissue by Alzheimer's patients. Preparation should be directed toward leaving the tissue as intact as possible. Alzheimer's Disease Therapy Recommendations- A Summary I suggest 10 mg of deprenyl be taken daily (5 mg with breakfast, 5 mg with lunch) for any Alzheimer's patient. I suggest the consumption of 2 grams of Acetyl-L-Carnitine daily in divided doses with meals by AD patients. I recommend the AD patient take three times daily with meals at least 400 i.u. of vitamin E, one half gram of vitamin C, 25,000 i.u. of beta carotene (or, even better, consumption of a high dose multivitamin) , and 200 mcg of selenium. Also take 120 mg Coenzyme Q10, and 120 mg B-6 in three divided doses. Additionally, the patient should try to maximize his/her consumption of fruits and green vegetables, striving for five to six servings a day. I suggest consumption of a magnesium supplement sufficient to provide 400-800 mg of elemental magnesium per day. Example: 2 tablets of magnesium chloride (OTC: Slo-Mag) three times a day (6 total/day) with meals. This will provide about 400 mg of elemental magnesium per day. I suggest nightly consumption of 6 to 10 mg melatonin just before going to sleep, and consumption of an additional 3 mg if the patient wakes up in the night with at least 4 hours of sleep to go. When timed-release melatonin becomes available, I suggest using that. I suggest daily hormone replacement therapy with DHEA (one capsule in the morning) to achieve youthful DHEA levels for Alzheimer's patients. I suggest pregnenolone supplementation of 30mg/day initially for Alzheimer's patients. Typical dosages vary from 10-100mg/day. I recommend daily or weekly consumption of small amounts of healthy animal brain tissue by Alzheimer's patients. Preparation should be directed toward leaving the tissue as intact as possible. If no antiinflammatory drugs are currently being taken by the Alzheimer's patient, I recommend one enteric-coated 325-mg aspirin be taken with breakfast, and one ibuprofen tablet be taken with dinner. If the disease continues to progress with all of the above therapy modalities, including aspirin and ibuprofen therapy, I recommend initial therapy with indomethacin (100-150 mg/day). Due to possible exacerbation of gastric problems, discontinue aspirin and ibuprofen therapy during indomethacin use. If indomethacin cannot be tolerated, then re-initiate aspirin and ibuprofin therapy, and try chronic administration of prednisone at low doses (10 mg/day or less). Commence a search for a nonsteroidal antiinflammatory drug which can be tolerated. References (Starred references [*] are included in this package) 1* Development of pharmacological treatments for Alzheimer- type dementia. (1994) J. Royal Soc. Med. 87:Supp. 23 2*. "Possible New Test Found for Alzheimer's Disease", Science: Vol 266, 11 Nov 1994, pp. 973 3*. "A Potential Noninvasive Neurobiological Test for Alzheimer's Disease", Science: Vol 266, 11 Nov 1994, pp. 1051-1053 4. Alternatives in the treatment of memory loss in patients with Alzheimer's Disease, Clin Pharm 1991 Jun;10(6):447-56 5. Deprenyl-medication: a strategy to modulate the age-related decline of the striatal dopaminergic system (1992) J Am Geriatr Soc Aug;40(8):839-847 6*. The pharmacological basis of the beneficial effects of deprenyl in Parkinson's and Alzheimer's diseases, J Neural Transm (1993) [Suppl]40:69-91 7. Clinical issues of cognitive enhancers in Alzheimer disease (1991) Alzheimer Dis Assoc Disord 5 Suppl 1:S25-31 8*. The Pharmacological Profile of Deprenyl and its Relevance for Humans: A Personal View (1992) Pharmacology & Toxicology 70:317-321 9*. Physicians Desk Reference (1994) Eldepryl 2309-2311 10*. Long-term efficacy and safety of deprenyl (selegiline) in advanced Parkinson's disease (1989) Neurology 39:1109-1111 11*. Combination of tacrine and selegiline in Alzheimer's disease: An open pilot study. 4th Int'l Conference on Alzheimers, S136 12*. Rationale for the use of selegiline in the treatment of Alzheimer's Disease. 4th Int'l Conference on Alzheimers, S66 13*. Acetyl-L-Carnitine: A Drug Able to Slow the Progress of Alzheimer's Disease? (1993) Ann NY Acad Sci, Vol. 640:228- 232 14*. Acetyl-Carnitine and Alzheimer's Disease (1992) Nutrition reviews, 50:5; 142-143. 15*. The role of oxidative abnormalities in the pathophysiology of Alzheimer's disease (1991) Rev Neurol 147(6-7):513-25 [Abstract only included] 16*. Free radicals in brain metabolism and pathology (1993) British Medical Bulletin 49:3;577-587 17*. Involvement of Free Oxygen Radicals in B-Amyloidosis: An Hypothesis (1994) Neurobiology of Aging 15:4; 443-455 18*. Effects of dopaminergic drugs on superoxide dismutase: implications for senescence (1993) J Neural Transm [Suppl]40:37-45 19. Neurology (Febuary, 1994) Author: Dr. John Breitner, Duke University 20* Discussion on tacrine (1994) Alzheimer Disease and Associated Disorders Vol 8, Suppl 2, pp. S58 21*. Coenzyme Q10, iron, and vitamin B6 in genetically- confirmed Alzheimer's Disease (1992) Lancet 340:671-672 22*. Magnesium Supplements (1994) Physicians Desk Reference 1793-1798 23*. Melatonin, hydroxyl radical-mediated oxidative damage, and aging: A hypothesis (1993) J. Pineal Res 14:151-168 24. Melatonin in human cerebrospinal fluid: Its origin and variation with age. Life Sci.(1979) 25:929-936 25*. Plasma melatonin rhythm in in normal aging and Alzheimer's Disease (1986) J. Neural Transm. Suppl. 21:494 26. Alterations in nocturnal serum melatonin levels in humans with growth and aging (1988) J. Clin. Endocrinol. Metab. 66:648-652 27. Daily variation in the concentration of melatonin and 5- methoxytryptophol in the human pineal gland: Effect of age and Alzheimer's Disease (1990) Brain Res. 628:170-174 28*. The pineal control of aging: The effects of melatonin and pineal grafting on the survival of older mice (1991) Ann. N.Y. Acad. Sci. 621:291-313 29. Pineal gland and aging (1991) Aging 3:103-116 30. The aging pineal gland and it's physiological consequences (1992) Bioessays 14:169-175 31. Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer's type dementia (1992) Neurosci. Lett. 141:9-12 32*. Pituitary-adrenocortical and pineal activities in the aged rat (1991) Ann. N.Y. Acad. Sci. 621:256-261 33. Antioxidant capacity of melatonin: A novel action not requiring a receptor (1993) Neuroendocrinol. Lett. 15:103-116 34*. Melatonin and sleep in humans (1993) J Pineal Res 15:1- 12 35. Barrett-Connor, E., K.T. Shaw, S.S.C. Chen (1986) New England J Med 315:1519 36*. Antiglucocorticoid Effects of DHEA-S in Alzheimer's Disease (1992) Am J Psychiatry 149:8, 1125-1126 37. Cognitive effects of corticosteroids (1990) Am J Psychiatry 147:1297-1303 38. DHEA-S serum levels in normal aging and Alzheimer's Disease (1991) Age 14:116-118. 39*. Letter, reply to ref. 36, (1992) Am J Psychiatry 149:8, 1126 40*. DHEA Gets Respect (1994) Harvard Health Letter, July 1994 1-3 41*. Reduced plasma DHEA concentrations in Alzheimer's Disease (1989) Lancet ii:570 42*. DHEA- the mother steroid: Part I. Immunologic Action (1994) Annals NY Acad Sci. 719:553-563 43*. Hormonal intervention: "buffer hormones" or "state dependency." The role of DHEA, thyroid hormone, estrogen and pypophysectomy in aging. Annals NY Acad Sci. 521:260-273 44*. DHEA-S in the Oldest Old, Aged 85 and Older (1994) Ann NY Acad Sci 719:543-552 45*. The Endocrinology of Aging: Can we prevent senescence? (1994) Extro 1, pp. 101-128 46. Effects of adrenal androgens on the transplantable human prostate tumor, Endocrinology 131:2909-2913 47*. Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it (1992) Proc Natl Acad Sci USA Mar 1;89(5):1567-71 48*. Inflammatory Mechanisms in Alzheimer's Disease (1994) Am J Psychiatry 151:8;1105-1113 49*. 45th Forum in Immunology: Immunological factors in Alzheimer's Disease: Implications for therapy (1992) Res. Immunol. 143:675-683 50*. Cerebrospinal fluid antibodies: an indicator for immune responses in Alzheimer's disease (1992) Res Immunol. 143:663-667 51*. Neuroimmune Mechanisms in Alzheimer disease Pathogenesis (1994) Alzheimer Disease and Associated Disorders 8:3;149-158 52*. New Alzheimer's Therapy Suggested (1993) Science:260;18 Jun, pp. 1719-1720 53*. Clinical trial of indomethacin in Alzheimer's disease (1993) Neurology Aug;43(8):1609-11 54*. Indomethacin and Indocin (1994) Physicians Desk Reference, 1472-1473 55*. Oral tolerance: Immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens (1994) Annu Rev Immunol.12:809-37 56*. Double-Blind Pilot Trial of Oral Tolerization with Myelin Antigens in Multiple Sclerosis (1993) Science 259:1321-1324 Alzheimer's Disease- Recommended Action Checklist Make an appointment with an opthalmologist and have the eye test performed. If the results are positive, make an appointment with your physician. Bring the results of the patients eye test and this package Attempt to get his/her cooperation in your program. If you have health insurance, try to get a prescription for deprenyl and DHEA. Seeif any other listed compounds could also be obtained via prescription so that your health insurance pays for it. Discuss the advisability of commencing Indomethacin or other nonsteroidal antiinflammatory drug therapy. What you can do without your physician: Everything except Indomethacin or other prescription nonsteroidal antiinflammatory drug therapy. If you are unable to have the eye test done, and don't wish to involve a physician, everything recommended here has general anti-aging effects, and can be followed by most elderly persons who wish to retain their health. Either in consultation with your physician, or on your own, order the following products, and begin taking at the recommended dosages: 1. From Beyond-A-Century: 1-800-777-1324, phone credit card orders accepted. 200.2- Life extension mix, low niacin. If you can't take fairly large tablets, they do have loose powder which can be mixed with water. 4 bottles of 315 tablets- $138 8 bottles of 315 tablets- $245 204.0- Selenium complex. 1 or 2 bottles of 200mcg x 100 tablets- $5 each Optional but recommended: 003.5- Performance Extra- Arginine/OKG 2:1 mix, 250 gram bottle- $28.75 each 2. From Healing Alternatives Foundation: Use enclosed photocopy of order form. Must mail-order. Credit cards or checks accepted. Coenzyme Q-10 (150) 1 or 2 bottles 30mg x 100 capsules- $19.42 (Calif. residents $20.95). DHEA-100 1 or 2 bottles 250mg x 100 capsules- $62.87 (Calif. residents $67.81). OR: If you have health insurance and your doctor is willing, get your doctor to prescribe DHEA as hormone replacement therapy at his recommended dosage and get from your local pharmacy. OR: If you would rather use a credit card and place a phone order for DHEA, try: Atlanta Buyer's Club (404) 874-4845 AIDS Buyer's Club, takes phone credit card orders. DHEA- 250mg x 100- Approx. $60. 3. From Life Extension Foundation: 1-800-841-5433, phone credit card orders accepted. Melatonin 1 or 2 bottles 10mg x 60 capsules- $24 each 1 or 2 bottles 3mg x 60 capsules- $8 each Acetyl-L-Carnitine 2 to 4 bottles 500mg x 100 capsules- $68 each 4. From A. Werner & Co. PO Box 615 11121 Prague 1 Czech Republic Mail orders only, use included photocopy of order form. Send airmail. Checks or (recommended) money orders accepted. Could be up to 45 days for delivery, so order sufficient quantity. Need 2 capsules per day. Deprenyl-100x5 mg capsules-$95, 400x5 mg capsules-$360 Plus $7 shipping. OR: If you have health insurance and your doctor is willing, get your doctor to prescribe Deprenyl/Selegiline/Eldepryl, 10mg per day, and get from your local pharmacy. 5. From Lifelink 445 Liery Lane Arroyo Grande, CA 93420 (805)473-1389 Pregnenolone: 30mg x 50- $33, or 30mg x 150- $90, or 30mg x 500- $270, prescription not required. Plus $4 shipping. 6. From Local Drug Store: 1 bottle enteric-coated aspirin, 325 to 400 mg tablets- Approx. $6 1 bottle Ibuprofin- Approx. $6 7. From Local Meat Market Fresh, healthy animal's brains. Begin consuming a small amount daily or weekly. Note: All of the above compounds should be refrigerated prior to use, with the exception of Deprenyl, which should be stored at room-temperature. Alzheimer's Disease- Treatment Resources 1. Melatonin- Cost/Day: $0.13 to $0.26. Dosage: One to three 3 mg capsules or one 10 mg capsule 1/2 hour before sleep, plus an. additional 3 mg capsule if you wake up with at least 4 hours to go. Source: Life Extension Foundation (1-800-841- 5433), Vitamin Research Products, or Beyond-A-Century. 2. Life Extension Mix- Cost/Day: $1.09 to $0.88 (depending on whether 1,4, or 8 bottles of 315 tablets are bought at once). Dosage: 3 tablets with each meal (9 per day). Source: Beyond-A-Century. Life Extension Mix (LEF) contains the following components which are specifically called for in my Alzheimer's Treatment Strategy: Numerous generalized antioxidant and immune system boosting compounds (vitamins C, E, etc.) Vitamin B-6: 200 mg Magnesium (in chloride, aspartate, and succinate forms): 1 gram Selenium (in sodium selenate and methionine complex): 100 mcg Contains 50 antioxidant ingredients based on latest scientific and medical research. Example: Vitamin E was shown in a very large study to be associated with a 37% reduction in risk of coronary disease in men and a 41% reduction for women. Formula updated regularly. One of the best high doseage multivitamins on the market. This formula is not like a typical multivitamin that you can get at a drug store, in two important ways: 1. The sophistication of the formula, and 2. The total amounts. L.E. Mix contains far more of each component than a typical multivitamin. Example: to have the anti-arteriosclerotic effect of vitamin E mentioned above, you need to take at least 100 i.u. (International Units- a measure of bioactivity) of vitamin E per day. A typical mulitvitamin has perhaps 37 i.u. L.E. Mix has 600 i.u. of vitamin E. Current formula of Life Extension Mix- 9 tablets, capsules or powder in three divided doses with meals: Vegetable Complex Beta-Carotene (ROCHE)- 25,000 i.u. Xanthophyll complex- 7500 i.u. Lycopene complex- 10,000 i.u. Broccoli concentrate- 500 mg Cabbage concentrate- 500 mg Vitamin A- 5000 i.u. B Complex B1 (Thiamin HCL)- 250 mg B2 (Riboflavin)- 50 mg B3 (Niacin 75 mg, Niacinamide 100 mg)- 175 mg B5 (Calcium pantothenate)- 750 mg B6 (pyridoxine HCL)- 200 mg B12 (ion exchange resin)- 100 mcg PABA- 50 mg Folate Triglutamate- 800 mcg Biotin- 200 mcg Ascorbate Complex Vitamin C (from Calcium, Magnesium, and niacinamide ascorbates)- 2500 mg Ascorbyl palmitate- 500 mg Acerola juice powder- 300 mg Tocopherol Complex Vitamin E (D, L- alpha tocopherol acetate)- 300 i.u. Vitamin E (D- alpha tocopherol succinate)- 300 i.u. Amino Acid Complex L-taurine- 500 mg N-acetyl-cysteine- 200 mg L-glutathione- 15 mg Mineral Complex Magnesium chloride- 800 mg Magnesium aspartate- 100 mg Magnesium succinate- 100 mg Potassium aspartate- 50 mg Potassium chloride- 49 mg Calcium citrate- 500 mg Calcium stearate- 250 mg Vitamin D- 200 i.u. Selenium (sodium selenate)- 50 mcg Selenium (seleno-methionine Nutr 21)- 50 mcg Optizinc (tm)- 20 mg Zinc succinate- 15 mg Chromate (tm) (GTF chromium niacin bound)- 50 mcg Chromium picolinate- 50 mcg Plus Cholinergic and Flavinoid Complexes. I will assume that the patient is taking this formulation in recommending doses for the following supplememental compounds. 3. Enteric Coated Aspirin- Cost/day: pennies. Dosage: 1 325mg tablet/day with breakfast. Source: Any drugstore. Low-dosage aspirin has a dramatic effect on lowering heart disease. In a study of 22,071 physicians over a 60 month period, those doctors over 50 years of age taking aspirin had a 44% reduction in heart attacks. In people with pre-existing heart disease, aspirin reduced the risk by 47%. Those people with heart disease that took both aspirin and beta carotene had NO heart attacks. It also has an effect on cancer apparently by reducing "platelet-aggregability", or the tendency of cells to attach to other cells. This is how it prevents heart disease (arteriosclerosis), and how it also inhibits cancer's "metastasizing", or spreading, because the cancer cell which floats free must anchor itself somewhere to begin growing again. Aspirin should be used cautiously if at all by persons with diabetic retinopathy or poorly controlled high blood pressure; i.e., those at risk of bleeding-type disorders. 4. Ibuprofin- Cost/day: pennies. Dosage: 1 tablet/day with dinner. Source: drug store. Ibuprofin is an anti-inflammatory drug. People who use ibuprofin chronically (every day) tend to get Alzheimer's Disease at lower rates than those who don't. 5. Deprenyl or Eldepryl- Cost/day: $1.80 to $4.80. Dosage: 10 mg/day. One 5 mg tablet with breakfast, one with lunch. Source: local pharmacy with prescription (100 x 5mg- $220) or, much cheaper, without prescription, A. Werner & Co. (100 x 5mg-$95, 400 x 5mg-$360) 6. DHEA- Cost/day: $0.68 to $2.00. Dosage: approximately 100-250 mg/day. Source: Most (not all) local compounding pharmacies($2 for a 100 mg capsule), or Lifelink (25mg x 180- $40, 195mg x 50- $40, 195mg x 150- $108, 195mg x 500- $340), or, cheapest, Healing Alternatives Foundation (250mg x 100- $67.81) or Atlanta Buyer's Club (250mg x 100- approx $60) 7. Selenium complex- Cost/day: pennies. Dose- Two tablets/day. Source: Beyond-A-Century (200mcg x 100- $5) 8. Acetyl-L-Carnitine- Cost/day: $2.72. Dose- Four 500 mg capsules/day. Two with breakfast, and one with lunch and dinner. Source: Life Extension Foundation. 9. Pregnenolone- Cost/day: $0.60. Dose- 10 to 100 mg; start with 30mg. Source: Lifelink. 10. Coenzyme Q10- Cost/day: $0.75 to $0.56. Dose- Four 30 mg capsules/day. Two with breakfast, one with lunch and dinner. Source: Beyond-A-Century, or, cheapest, Healing Alternatives Foundation. 11. Magnesium- Cost/day: $0.10 to $1.50. Dose- None, if taking Life Extension Mix. Otherwise, two tablets magnesium chloride or one tablet magnesium oxide with each meal. Source: drugstore. 12. Vitamin B-6. Cost/day: pennies. Dose- None, if taking Life Extension Mix. Otherwise, 250mg/day. Source: Drugstore or mail-order vitamin supply. 13. Nonsteroidal Anti-Inflammatory Drug- Ex.- Indomethacin. Cost/day: unknown. Dose Depends on compound. For Indomethacin, 100-150 mg/day. Source: Local pharmacy, doctor prescribed. 14. Fruits & Vegetables In Your Diet A large study, published April 14, 1994, tested whether high- dose beta carotene and/or a small dose of vitamin E taken for five years by men who had smoked for at least 30 years would reduce lung cancer. It did not. Carcinogenesis may take longer than 5 years; if so, the vitamin intake was started too late. Beta carotene has been shown in other studies to prevent impairment of the immune system by UV light and inhibit mouth and cervical cancer. In another study, beta carotene reduced the risk of heart attacks in people with preexisting heart disease by 41%. People with heart disease that took both aspirin and beta carotene had NO heart attacks. The evidence supports taking some beta carotene, and Life Extension Mix contains this compound. The amounts of vitamin E used in the study were not enough to have any effects, based on amounts used in previous studies, so the study has no relevance on vitamin E's effectiveness or lack thereof. Bottom line, the substances in fruits and vegetables which prevent cancer have not yet been completely identified. It may also be that diets high in fruits & vegetables are also low in fat, which may be a contributing factor for cancer reduction. Therefore, good judgement dictates that in addition to strategic supplements, one should try to eat as many fruits & vegetables as possible. OPTIONAL BUT RECOMMENDED: 15. Growth Hormone Releaser-Cost/Day: $.48. Performance Powder Extra (Arginine/Ornithine alpha-keto glutamate (OKG)) 2:1 mix, 300 gram package, cat. no. 003.5, $28.75 for 300 grams). Dosage: Men-2 level tablespoons. Women-1 level tablespoon. Source: Beyond-A-Century. As you age, your body's production of growth hormone declines. Certain amino-acid formulations can stimulate growth hormone release if taken at the proper time and on an empty stomach. The idea is to mimic the natural release of growth hormone by a young person. GH is normally released in reaction to two events: maximum effort exercise (not just jogging, but the 100 yard dash, for example), and sleep. Take on an empty stomach just before going to bed (stomach acids associated with foods, especially sugar, destroy the amino acids). Start with a low dosage and work your way up. Benefits for both men and women include more rapid healing, a leaner, more muscular body, and significantly increased immune response (ability to fight off disease in all it's forms- from colds to cancer). When taken before sleep, it increases REM sleep and may produce a sense of well-being. It should not be taken by someone who has existing cancer. Arginine has recently been associated with nitric oxide metabolism in the human body. Nitric oxide appears to be very important for many basic processes, including blood pressure. Arginine lowers blood pressure, perhaps because it is a precursor of NO. Arginine is being added to some intraveinous solutions given surgery patients after surgery in an attempt to speed healing time. Resources Beyond-A-Century PO Box 713 Greenville, ME 04441 1-800-777-1324 Products offered- most. Free catalog. Life Extension Mix: Bottle of 315 tablets (35 days worth)- $30.62 if 8 bottles bought. Selenium: 100 x 200 mcg selenium complex-$5 Plus $4.50 shipping. Life Extension Foundation PO Box 229120 Hollywood, FL 33022-9120 1-800-841-5433 Melatonin: 60 x 3mg: $8, 60 x 10mg: $24 Acetyl-L-Carnitine: 100 x 500mg: $68 Vitamin Research Products 3579 Hwy 50 East Carson City, NV 89701 (702) 884-1300 & (800) 877-2447 fax-(800) 877-3292 Products offered-most. A research and vitamin formulation sales company similar to LEF Outstanding free research newsletter/catalog. Appear to be a conscientious company with integrity. Lifelink 445 Liery Lane Arroyo Grande, CA 93420 (805)473-1389 DHEA-25mg x 180: $40, 195mg x 50: $40, 195mg x 150: $108, 195mg x 500: $340, prescription not required. Pregnenolone: 10mg x 90: $20, 30mg x 50: $33, 30mg x 150: $90, 30mg x 500: $270, prescription not required. Plus $5 shipping. Atlanta Buyer's Club (404) 874-4845 DHEA- 250mg x 100: approx $60, phone credit card orders taken. Healing Alternative Foundation 1748 Market Street, Suite 205 San Francisco, CA 94102 (415)626-2316 Free catalog. AIDS buyers club: must join ($1 first time you order) DHEA: 100 x 250mg capsules: $62.87 ($67.81 for Calif. residents) Coenzyme Q-10: 150 x 30mg: $19.42 ($20.95 for Calif. residents) Plus $6 shipping. A. Werner & Co. PO Box 615 11121 Prague 1 Czech Republic Deprenyl-100x5 mg capsules-$95, 400x5 mg capsules-$360 Plus $7 shipping. Eye Test for Alzheimer's Disease: Procedure 1) Prepare a dilute solution of tropicamide (0.01%). 2) Have the patient sit in a semidarkened room for 2 or 3 minutes. Measure the resting pupil diameter for 1 minute. Record the average value on the data sheet. Then administer one drop of the dilute solution of tropicamide to one eye. Note the time. Begin timing from this point. 3) Examine the eye for pupil diameter for 30 seconds at the following times after drop administration and record the average value of pupil diameter on the data sheet. Times: 2, 8, 15, 22, 29, 41, and 51 min after drop administration. 4) Perform the calculations indicated on the data sheet to convert raw pupil diameter measurements to percentage changes from the baseline, or initial measurement. 5) Plot the percentage changes at the measurement times on the included graph. Compare the profile with the already plotted profiles of Alzheimer's patients and healthy controls. Which profile more closely matches the patients profile? 6) If the profile does not indicate Alzheimer's Disease, then consider the possibility of non-Alzheimer's dementia, such as Korsakoff's syndrome, multi-infarct demetia, and dementia with an extrapyramidal syndrome, and get a doctor's advice on diagnosing and treating the problem. If the profile more closely matches the AD patient's profile, then proceed with the course of treatment indicated herein, in consultation with a physician. --========================_7573406==_--