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Delaying The Onset and Progression of Alzheimer’s Disease DELAYING THE ONSET AND
PROGRESSION OF ALZHEIMER’S DISEASE

INTRODUCTION

Recently, the Quality Standards Subcommittee of the American Academy of Neurology reviewed the evidence-based
medicine published data on the costs and benefits of detecting dementia early. Based on this review, they
recommended that persons with mild cognitive impairment be further evaluated and monitored(1). Mild cognitive
impairment is now known to greatly increase the risk of developing dementia due to Alzheimer’s disease and related
disorders (ADRD).
Current methods of prevention and treatment can significantly delay both the onset of symptoms and the progression
of Alzheimer’s disease (AD). Through a combination of family education, drug and antioxidant therapy and lifestyle
changes, the effects of this disease can be delayed for three to six years, without extending life expectancy (see
below). The result is improved quality of life, reduced costs and a lower need for both formal and informal care for
victims of this disease.
According to H. M. Fillit, executive director of the Institute for the Study of Aging, “in the long term, drug therapy
for AD reduces overall expenses by decreasing hospitalization and institutionalization rates, diminishing caregiver
burden, and helping to control comorbid conditions(2)”. This is consistent with data from The National Long-Term
Care Survey, which suggests that a greater degree of cognitive impairment at time of diagnosis associates with higher
total cost of care and longer duration of residence in a nursing home(3).
Unfortunately, dementia is not an easy condition for either families or physicians to deal with. Detection of dementia
due to AD and other causes in the primary care setting usually occurs 2 to 4 years after symptom onset, if at all. A
recent study found that 75% of moderate and severe dementia cases and >95% of mild dementia cases are not
detected in the primary care setting(4). Furthermore, even when dementia is detected, about 75% of physicians do
not use the standardized criteria needed to accurately diagnose AD(5).
This difficulty of detecting dementia in primary care settings points to the clear need for services that can assist
patients, families and physicians in detecting, diagnosing and treating AD without the need for added time and effort
on their part. In spite of the clinical advances in AD diagnosis and treatment, primary care physicians still do not
have the mechanisms to apply such knowledge in a useful way within the context of their practice. Medical Care
Corporation provides this mechanism. By coupling its automated, interactive, online healthcare system with the most
currently available knowledge, Medical Care Corporation consistently facilitates the most favorable clinical results
and significant cost savings.
SUMMARY OF MAIN POINTS

• Preventative therapy delays the onset of AD symptoms by 3.5 years(6), which would reduce AD prevalence • Early detection and treatment delays progression by at least 2.8 years, which usually will eliminate need to Medical Care Corporation 2004 All Right Reserved It is prohibited by law to reproduce, copy or use the entire article or any parts of it for any reason at any time. If you wish to use any contents of this article, please submit your request in writing to Medical Care Corporation, 19782 MacArthur Blvd., Suite 310, Irvine, CA 92612. Delaying The Onset and Progression of Alzheimer’s Disease • Delaying onset and progression of AD gives affected persons six more years of good quality life without • At present, total costs of AD are more than $110 billion per year(8). Opportunity costs for the caregiver, such as lost wages, and retirement benefits, exceed $20 billion per year(9). • Shortening institutionalization by one month saves $2,000(2). Delaying AD by six years would save between $150,000 and $300,000, and allow affected individuals to live out their life at home. PRINCIPLE FINDINGS

PREVENTION OF ALZHEIMER’S DISEASE AND RELATED DISORDERS

Non-steroidal Anti-inflammatory Drugs (NSAIDs)
9 of 10 population-based studies have shown that NSAIDs used in low doses for two or more years(10) in persons
under 80 years old reduce the chance of developing AD by about 50%(10-15). Low dose means <175 mg aspirin or
<500 mg Naproxyn or equivalent dose with other NSAIDs(10). The efficacy of aspirin varies between different
studies. Many show about a 30% risk reduction, while the Rotterdam study did not show a risk reduction and the
Australian study showed risk reduction comparable to other NSAIDs. Because high and low doses are equally
effective, reducing inflammation does not appear to be the mechanism by which NSAIDs reduce risk. Low doses of
certain NSAIDs (ibuprofen (i.e., Motrin, Advil); Sulindac; and indomethacin (Indocin)) inhibit the production of ß-
amyloid, which is a key component of AD pathology(12).
Mild cognitive impairment is now thought to be an early symptomatic stage of AD and other dementing disorders in
many individuals. Data from the Established Populations for Epidemiologic Studies of the Elderly (EPESE) showed
that persons taking low to moderate doses of NSAIDs performed better on the Short Portable Mental Status
Questionnaire than persons not taking NSAIDs or taking high doses of NSAIDs. The magnitude of this effect was
estimated to delay the onset of cognitive decline by 3.5 years(6). Since the prevalence of AD doubles every five
years after age 65, the delay of pre-symptomatic AD with current preventive therapy could reduce overall disease
prevalence by 35%.
To take advantage of such enormous benefits, the potential complications of preventive therapy need to be minimized
and individuals need easy access to the most current preventive measures. Medical Care Corporation’s preventive
service individually tailors recommended interventions based on medical histories and profiles, and periodically
updates these recommendations based on new preventive knowledge. Medical Care Corporation’s screening and
cognitive monitoring service works in conjunction with its prevention service by screening individuals each time they
seek to update their prevention therapy.
Statins
The largest study conducted to date examining the association between statin use and risk of Alzheimer’s disease was
done by researchers from Boston University School of Medicine. They compared the risk factors and medication
history between 912 AD patients and 1669 of their normal aging family members. After adjusting for a number of
factors, including age, sex, ethnicity, and apolipoprotein E genotype, the relative risk of AD among statin vs. non-
statin users was 0.21 (a 79% risk reduction). Other cholesterol-lowering drugs did not show a statistically significant
reduction in the relative risk for AD. Further support of this protective effect of statins came from the Canadian
Health Study of the Aging(16). 492 Canadians over 65 years old developed dementia after their initial assessment,
and were compared to 823 persons who remained normal. After controlling for smoking and hypertension, the
relative risk for AD among statin users was 74% less than non-statin users under 80 years old (odds ratio, 0.26; 95%
Medical Care Corporation 2004 All Right Reserved It is prohibited by law to reproduce, copy or use the entire article or any parts of it for any reason at any time. If you wish to use any contents of this article, please submit your request in writing to Medical Care Corporation, 19782 MacArthur Blvd., Suite 310, Irvine, CA 92612. Delaying The Onset and Progression of Alzheimer’s Disease CI = 0.08-0.88). These results are also consistent with a recent meta-analysis of seven studies in the literature, which
showed that statin use reduces overall risk of cognitive impairment by 57% (relative risk = 0.43, 95% CI 0.31-0.62),
while other lipid lowering agents do not show a statistically significant reduction in risk of cognitive impairment
(relative risk = 0.62, 95% CI = 0.28-1.38)(17).
Vitamin E
A 3-year longitudinal within-subject study of 2,889 community residents 65 to 102 years old examined working
Memory, short-Term Memory, global mental status and complex task performance. The study found that persons
who took an Vitamin E: 400 iu/day or higher showed a 1/3 reduction in their rate of cognitive decline compared to
those who took little or no Vitamin E(18).
Vitamin C and beta carotene showed no effect on rate of cognitive decline. Both dietary sources and supplements of
these antioxidants were measured.
DELAYING AD PROGRESSION

Aricept (Donepezil) - In one open label study, Donepezil was given to 133 mild to moderate AD patients for two or
more years. Based on cognitive testing using the ADAS-Cog, these patients declined at a rate of 3.3 points/year
compared to a rate of 9 points/year based on the natural history of untreated mild to moderate AD patients(19). This
study demonstrates a disease delaying effect that persists for at least two years.
Aricept vs. Reminyl – Both Aricept and Reminyl appear to operate by inhibiting acetylcholinesterase. In contrast to
Exelon, they inhibit butyrylcholinesterase relatively little. Aricept and Reminyl also bind to the presynaptic nicotinic
acetylcholine receptor, which increases presynaptic acetylcholine release, and increases release of many other
neurotransmitters. Although Reminyl has been marketed to be unique in its allosteric modulation of the nicotinic
acetylcholine receptor, a study funded by the manufacturers of Reminyl suggests otherwise. Aging rats administered
either Reminyl or Aricept showed a similar increase in long-term potentiation in the hippocampus during an episodic
memory task (Morris water maze). Furthermore, Aricept bound more tightly to the nicotinic acetylcholine receptor
than did Reminyl(20). The potential significance of nicotinic acetylcholine receptor binding is that it blocks
programmed neuronal cell death (apoptosis) in experimental animal models. Also in animal and in vitro models,
apoptosis contributes to the neuropathology of AD and other neurologic disorders, including stroke, epilepsy,
Parkinson’s and others.
To date, the longest open-label study ever done consisted of 763 mild to moderate AD patients who had participated
in one of two double blind, randomized, placebo-controlled clinical trials for up to 30 weeks, followed by a placebo
washout for three to six weeks, then treatment with Aricept for 144 weeks. Compared to all other groups, the group
treated with 10 mg/day during the double blind portion of the study showed consistently better cognitive function for
at least 2.4 years (123 weeks as measured by the ADAS-Cog score). Furthermore, patients who had been washed out
for six weeks at the end of the double blind study irreversibly declined in cognitive function during this time. When
restarted on Donepezil however, AD progression was delayed (ADAS-Cog score), but they never caught up with the
group that was only washed out for three weeks.
Exelon (Rivastigmine) - Another study examined 532 mild to moderate AD patients who completed a six month
double blind trial of Rivastigmine vs. placebo and then took 6-12 mg/day of Rivastigmine for two more years. These
patients showed a decline of 4.2 points, which produced an estimated delay of AD progression of at least 2 years(21).
Exelon vs. Aricept – 382 mild-to-moderate AD patients who had failed Aricept ((80% due to lack of efficacy, 11%
due to tolerability problems, 9% both reasons), were switched to Exelon. 56.2% of patients were responders to
rivastigmine, as assessed using a global function scale (the Clinicians' Global Impression of Change). Cognitive
performance (measured by the Mini- Mental State Examination) and the ability to perform activities of daily living
(measured by the Instrumental Activities of Daily Living scale) were improved/stabilised in 48.9% and 57.0% of
Medical Care Corporation 2004 All Right Reserved It is prohibited by law to reproduce, copy or use the entire article or any parts of it for any reason at any time. If you wish to use any contents of this article, please submit your request in writing to Medical Care Corporation, 19782 MacArthur Blvd., Suite 310, Irvine, CA 92612. Delaying The Onset and Progression of Alzheimer’s Disease patients, respectively(22). These patients either did not tolerate Aricept or were declining on Aricept. Approximately
50% of these patients showed significant stabilization or improvement when switched to Exelon. This study is
consistent with the finding that butyrylcholinesterase, which is found inside neuritic AD plaques and may convert
Amyloid Precursor Protein to beta amyloid, needs to be inhibited to improve function and slow AD progression.
Memantine (Namenda) -
Memantine has been approved by the FDA for treatment of moderate-to-severe AD. Memantine blocks the N-Methyl
D-Aspartate (NMDA) receptor from permitting calcium ion entry when synaptic activity is relatively low (e.g., -50
mV membrane potential), but is decoupled from the NMDA receptor when synaptic activity increases (e.g., -30 mV
membrane potential). This action effectively improves the signal-to-noise level as well as theoretically reduces the
chance of glutamate-mediated excitotoxicity, which can trigger programmed neuronal death (apoptosis). Reduction
of apoptosis via Memantine has been shown clinically in an MR Spectroscopy study of HIV patients (unpublished
report, S. Lipton et al.). Whether it also delays AD progression by blocking glutamate-mediated apoptosis or some
other mechanism has not yet been proven.
DELAYING INSITUTIONALIZATION
Cholinesterase Inhibitors (ChEI)
Tacrine was the first cholinesterase inhibitor approved to treat AD. A two year study comparing high doses (80 to 160
mg/day) to low doses (<80 mg/day) in mild to moderate AD patients showed that the patients on high doses were 1.75
times less likely to be placed into a nursing home after two years of treatment(23). Time to death did not differ
between the two groups.
Vitamin E and Selegeline
The Alzheimer’s disease Cooperative Study Unit demonstrated that AD patients treated for two years with either
selegiline (5 mg BID) or vitamin E (1,000 I.U. [alpha-tocopherol] BID) significantly delayed AD progression, and
that vitamin E delayed institutionalization by approximately 1 year(24).
Caregiver Support
A randomized clinical trial of mild-to-moderate AD patients showed that counseling and educating caregivers
combined with support groups delayed time to nursing home placement by about a year. The greatest benefits
occurred when patients were mild or moderately demented(25). Based on this and other studies, the American
Academy of Neurology Quality Standards subcommittee currently recommends short- and long-term programs
directed toward supporting and educating family caregivers about AD in order to delay time to nursing home
placement.
ChEI treatment has direct effects on amount of caregiving time. A one year randomized study of donepezil vs.
placebo showed that caregivers spent 12 hours per day taking care of AD patients receiving placebo, whereas those
receiving donepezil required 10.1 hours of caregiving daily. This difference amounted to an extra 10 weeks of work
per year for untreated AD patients(26).
COSTS OF ALZHEIMER’S DISEASE

In 2000, the estimated number of persons with AD in the USA ranged from 3.1 million to 4.8 million(8). Annual
formal and informal costs of caring for AD patients range from $15,360 to $65,885 in year 2000 dollars (midpoint =
$40,622), giving an estimated $111.9 billion yearly cost of caring for AD in the USA(27).
Medical Care Corporation 2004 All Right Reserved It is prohibited by law to reproduce, copy or use the entire article or any parts of it for any reason at any time. If you wish to use any contents of this article, please submit your request in writing to Medical Care Corporation, 19782 MacArthur Blvd., Suite 310, Irvine, CA 92612. Delaying The Onset and Progression of Alzheimer’s Disease The average cost of formal care due to physician and emergency room visits, hospitalization, medications and long-
term care, is $27,672, and increases with dementia severity(28). The costs of unpaid caregiving ranges from $10,400
to $34,517 annually, which accounts for 60% of caregiving costs, and can be up to 70 hours per week(9). Lost wages
for patient and caregiver plus increased medical costs related to caregiver illness are $50,000/year, or a total of $21
billion annually in the USA(29).
For mild and moderate AD patients, the most significant factor affecting cost of care is the presence of comorbid
conditions, with 93% of patients having at least one comorbidity, and 60% having at least three(30). The cost of
caring for comorbid conditions in AD are $3000 per year higher than age-matched patients,(31). AD patients visit the
emergency room twice as often as non-demented, age-matched patients, and are hospitalized an average of 16 days
longer, which costs $2500 more per hospitalization(32).
Treatment with ChEI for as little as six months and for as long as two years reduces the chance of being admitted to a
long-term care facility by about 50%(23). Even though the cost of ChEI is about $120 per month, the disease
delaying effect is cost effective because home care costs only 25% that of formal care in long-term care facilities(2,3).
This results in an estimated $2,000 savings per patient for each month that institutionalization is delayed(2).
CONCLUSIONS

From a logical and evidence-based medicine perspective, there is no longer any question whether early detection and
treatment is both humane and cost-effective for families, patients, physicians, healthcare providers and payers. The
challenge of delivering cost-effective dementia healthcare has arrived. The principle barriers to such delivery will be:
Educating the public about the value of prevention, early detection and treatment. Providing physicians with the patient-specific knowledge needed to detect, diagnose, treat and manage each patient to maximize the delay in disease progression. Implementing this knowledge delivery within the constraints of today’s managed healthcare settings. Medical Care Corporation 2004 All Right Reserved It is prohibited by law to reproduce, copy or use the entire article or any parts of it for any reason at any time. If you wish to use any contents of this article, please submit your request in writing to Medical Care Corporation, 19782 MacArthur Blvd., Suite 310, Irvine, CA 92612. Delaying The Onset and Progression of Alzheimer’s Disease 1. Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56: 1133-42, 2001. 2. Fillit H. Treating Alzheimer’s Disease and the economic impact on managed care. Clinical Geriatrics 10-3, 3. Kinosian BP SELJ. Predicting 10-year requirements for older people with suspected Alzheimer’s disease. J Am 4. Gifford DR, Cummings JL. Rating dementia screening tests: methodologic standards to rate their performance. 5. Somerfield MR WCU. Physician practices in the diagnosis of dementing disorders. J Am Geriatr Soc 39: 172-5, 6. Rozzini R, Ferrucci L, Losonczy K, Havlik RJ, Guralnik JM. Protective effect of chronic NSAID use on cognitive decline in older persons. J Am Geriatr Soc 44: 1025-9, 1996. 7. Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol 58: 427-33, 2001. 8. Kawas C, Katzman R. Epidemiology of Dementia and Alzheimer's Disease. In: Terry RD, Katzman R, Bick KL, Sisson RA, eds. Alzheimer Disease. Philadelphia: Lippincott Williams & Wilkins, p. 95-117, 1999. 9. Max W. Alzheimer’s disease: the unpaid burden of caring. J of Aging and Health 7: 179-99, 1995. 10. Broe GA, Grayson DA, Creasey HM, Waite LM, Casey BJ, Bennett HP, Brooks WS, Halliday GM. Anti- inflammatory drugs protect against Alzheimer disease at low doses. Arch Neurol 57: 1586-91, 2000. 11. Breitner JC, Gau BA, Welsh KA. Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study. Neurology 44: 227-32, 1994. 12. Andersen K, Ott A, Hoes AW, Launer LJ, Breiteler MB, Hofman A. Do nonsteroidal anti-inflammatory drugs decrease the risk of Alzheimer's disease? Neurology 45: 1441-5, 1995. 13. Stewart WF, Kawas C. Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48: 626-32, 1997. 14. McGeer PL, McGeer E, Rogers J. Anti-inflammatory drugs and Alzheimer’s disease. Lancet 335: 1037, 1990. 15. Broe GA, Creasey H, Jorm AF, Bennett HP, Casey B, Waite LM, Grayson DA, Cullen J. Health habits and risk of cognitive impairment and dementia in old age: a prospective study on the effects of exercise, smoking and alcohol consumption. Aust N Z J Public Health 22: 621-3, 1998. 16. Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R, Wolfson C, McDowell I. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 59: 223-7, 2002. Medical Care Corporation 2004 All Right Reserved It is prohibited by law to reproduce, copy or use the entire article or any parts of it for any reason at any time. If you wish to use any contents of this article, please submit your request in writing to Medical Care Corporation, 19782 MacArthur Blvd., Suite 310, Irvine, CA 92612. Delaying The Onset and Progression of Alzheimer’s Disease 17. Etminan M, Gill S, Samii A. The role of lipid-lowering drugs in cognitive function: a meta-analysis of observational studies. Pharmacotherapy 23: 726-30, 2003. 18. Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Vitamin E and cognitive decline in older persons. 19. Rogers SL, Doody RS, Pratt RD, Ieni JR. Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: final analysis of a US multicentre open-label study. Eur Neuropsychopharmacol 10: 195-203, 2000. 20. Barnes CA, Meltzer J, Houston F, Orr G, McGann K, Wenk GL. Chronic treatment of old rats with donepezil or galantamine: effects on memory, hippocampal plasticity and nicotinic receptors. Neuroscience 99: 17-23, 2000. 21. Farlow MR. Do cholinesterase inhibitors slow progression of Alzheimer's disease? Int J Clin Pract Suppl 37-44, 22. Auriacombe S, Pere JJ, Loria-Kanza. Efficacy and safety of rivastigmine in patients with Alzheimer's disease who failed to benefit from treatment with donepezil. Curr Med Res Opin 18: 129-38, 2002. 23. Knopman D. Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group. Neurology 47: 166-77, 1996. 24. Sano M. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. New 25. Mittelman MS, Ferris SH, Shulman E, Steinberg G, Levin B. A family intervention to delay nursing home placement of patients with Alzheimer disease. A randomized controlled trial. Jama 276: 1725-31, 1996. 26. Feldman H, Gauthier S, Hecker J, Vellas B, Emir B, Mastey V, Subbiah P. Efficacy of Donepezil on Maintenance of Activities of Daily Living in Patients with Moderate to Severe Alzheimer's Disease and the Effect on Caregiver Burden 27. Progress Report on Alzheimer's Disease. 1998. Bethesda, MD, National Institute on Aging. Ref Type: Report 28. Leon J. Alzheimer’s disease care: costs and potential savings. Health Aff (Millwood ) 17: 206-16, 1998. 29. Ernst RL HJ. The US economic and social costs of Alzheimer’s disease revisited. Journal Ti > Amer. J. of 30. Doraiswamy PM, Leon J, Cummings JL, Marin D, Neumann PJ. Prevalence and impact of medical comorbidity in Alzheimer's disease. J Gerontol A Biol Sci Med Sci 57: M173-M177, 2002. 31. Gutterman EM MJL. Cost of Alzheimer’s disease and related dementia in managed-medicare. J Am Geriatr 32. Torian LV DES. The effect of senile dementia on acute medical care in a geriatric medicine unit. Int Medical Care Corporation 2004 All Right Reserved It is prohibited by law to reproduce, copy or use the entire article or any parts of it for any reason at any time. If you wish to use any contents of this article, please submit your request in writing to Medical Care Corporation, 19782 MacArthur Blvd., Suite 310, Irvine, CA 92612.

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