Alzheimer' s Disease: A Summary of Research Findings -Part XVII

(1/28/09)- Researchers at Vanderbilt University concluded that long term usage of antipsychotic drugs pose a substantial risk to the elderly and the young. The results of the study were published in a recent edition of the New England Journal of Medicine.

The study also found that the risk of death increased for patients receiving larger doses of these drugs. Wayne Ray, a professor of preventive medicine at Vanderbilt was the lead investigator for the study.

The drugs involved in the study were Zyprexa made by Eli Lilly & Co., Risperdal made by J&J, Seroquel made by AstraZeneca PLC and .Clozaril, made by Novartis AG..

Researchers for the study reviewed the medical records of about 277,000 Tennessee Medicaid enrollees for the years 1990 to 2004. About 46,000 of them were taking atypical antipsychotic drugs and 44,000 were taking typical antipsychotic drugs. About 187,000 were not taking any of the drugs. Patients ranged in age from 30 to 74 years, with the average age being 46.

The researchers concluded that among patients taking the antipsychotic drugs, there were about three sudden cardiac deaths for every 1,000 patient-years. The death rate was about half that level for the control group of patients who were not taking any antipsychotic medications.

The study also found that the risk of death increased for patients receiving larger doses of both kinds of drugs.

(1/13/09)-The dementia antipsychotic withdrawal trial )DART-AD) long-term follow-up of a randomized placebo controlled trial study appeared in The Lancet Neurology, Early Online Publication, 9 January 2009. It was conducted by Clive Ballard et al "for the DART-AD investigators". These researchers looked at mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics. They were interested in mortality data from a long-term placebo-controlled trial.

Between October 2001, and December 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomized, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrolment of the last participant (range 24?54 months). Causes of death were obtained from death certificates.

The results indicated a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. The researchers concluded that there is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication. These results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in nursing homes.

Usually, antipsychotics are prescribed when a demented patient is agitated. It should be noted that The Physicians' Desk Reference (PDR) labels these medications with a blackbox warning indicating an increased risk of death and/or strokes in these patients. We recently reviewed a book, The Nursing Home Guide by Dr. Joshua D. Schor (look in our index under books) who expressed an approach well worth quoting. "Do I personally prescribe antipsychotics? Of course I do, but I do so cautiously and only after talking to staff and family. I do follow the rules of trying to wean the medications at least twice a year, unless there is a very compelling reason not to...If you get in a tussle with the physician, ask him or her to provide documentation that the proposed drug works and see what they say." (p. 139-140) The need for long-term care patient advocacy is an essential factor in enhancing quality of life in care facilities.

(5/24/06)- The February 2006 issue of the Archives of General Psychiatry published a study that indicated that Alzheimer's patients with a lifetime history of depression have increased plaques and tangles in the hippocampus section of the brain and more rapid cognitive decline into dementia than those who did not have depression. Present treatment outcomes for this type of patient is less favorable.

(7/3/02)-After writing 16 articles on various aspects of Alzheimer's disease, it would seem helpful to our readers to summarize what is known about the disease as reflected in the many peer reviewed studies published in the research literature. More detailed information on many of the items listed below can be found in the various articles in this series.

These conclusions are subject to future research findings, but represent the most recent state of knowledge in the field.

• Alzheimer' s disease is the most prevalent neurodegenerative disease and is considered nonreversible at present.
• Alzheimer' s disease involves progressive deterioration in intellectual abilities, namely loss of memory, and, finally, in loss of mental and physical function.
• Behavioral symptoms associated with Alzheimer' s disease include delusional thinking, suspiciousness, hallucinations, agitation, violence and verbal outbursts. Many of these symptoms may be amenable to pharmacological intervention.
• Roughly 7% of the population over 65 years of age has Alzheimer' s disease. (Common number used is 4 million in the United States.
• There are two types of Alzheimer's disease; early onset and late onset.
• Early onset familial cases of Alzheimer's disease are attributable to mutations on chromosome 21 or to presenilin 1 gene on chromosome 14, or presenilin 2 on chromosome 1. Accumulated evidence indicates that all these familial Alzheimer' s disease genes can induce death in neuronal cells or augment their vulnerability to other insults.
• Familial Alzheimer' s disease (early onset) is extremely rare, occurring in 5-10% of Alzheimer's disease cases.
• The role of genes in late onset may be to increase/modify the risk of developing Alzheimer' s disease by affecting factors involved in the formation of plaques and tangles or other Alzheimer' s disease related pathologies in the brain.
• Plaques are known to contain the B-amyloid protein as the major pathologic constituent. The neurofibrillary tangles are linked to a pathological relevant proteinaceous constituent known as the tau protein.
• The incidence of Alzheimer's disease rises with age over 65 at about 5% every 5 years.
• Mortality rates rise with increasing levels of cognitive decline.
• Risk factors for Alzheimer' s disease include increased age, the presence of apolipoprotein E- alleles, familial aggregation of cases and Down's syndrome. However, risk factors are not direct causes of the disease.
• A large body of data supports the hypothesis that amyloid B-protein plays a causal role in development of Alzheimer's disease, but is not sufficient to cause the disease. Beta amyloid is a fragment of a much larger protein known as amyloid-precursor protein (APP).
• Risk for Alzheimer's disease is known to be influenced by multiple genetic and environmental factors and aging. High fat diet may substantially elevate the risk of developing Alzheimer's disease.
• Cerebrovascular disease intensifies the presence and severity of Alzheimer's disease. In general, vascular disease is associated with cognitive impairment.
• Alzheimer's disease pathology commonly includes the occurrence of large numbers of neuritic plaques and fibrillary tangles.
• The onset of Alzheimer's disease is insidious and can be dated only within broad limits.
• People with mild cognitive impairment have an increased risk of developing Alzheimer's disease.
• The preclinical phase of Alzheimer's disease is the subject of intensive investigation. Cognitive symptoms and brain abnormalities (medial temporal lobe atrophy) are present many years before a clinical diagnosis.
• Medial temporal lobe atrophy, especially the hippocampus and parahippocampal gyrus regions, plays an important role in the storage of new information and may be sites of change preceding the expression of Alzheimer's disease symptoms.
• Women appear at higher risk for Alzheimer' s disease than men. One in eight men, and almost one in four women, will suffer at least some of their lifetime from Alzheimer's disease.
• Lower levels of education increases risk of Alzheimer's disease development.
• Depression is probably prodromal.
• Even on autopsy, it might be difficult to arrive at a definitive diagnosis.
• Head injury, a risk factor, may interact with ApoE gene, which is involved in various aspects of neurodegeneration and repair.
• Presence of ApoE4 gene, a variant of the ApoE lipoprotein, part of the bodies cholesterol transport system, does not invariably lead to Alzheimer' s disease. It is associated with increased serum total cholesterol levels, and with increased risk of artherosclerosis and coronary heart disease.
• Exposure to aluminum in the water supply may enhance the risk of Alzheimer's disease.
• Hypertension and other vascular symptoms appear to predispose to Alzheimer's disease.
• Potential protective factors include the use of non-steroid anti-inflammatory drugs to treat arthritis as well as estrogen use by post-menopausal women.
• Beta amyloid induces a local inflammatory reaction that contributes to the progression of Alzheimer's disease.
• Other protective factors include physical activity and diet with high levels of B6, B12, and folate, and moderate amounts of wine.
• The higher fraction of people who survive to 80 and beyond will drive up the frequency of the disease in coming years.
• There is no biological or chemical threshold beyond which Alzheimer's disease can be said to begin.
• Only about one-third of identical twins are concordant for Alzheimer's disease.
• Alzheimer's disease is characterized by cognitive deficits that involve cholinergic pathways. Cholinergic pathways comprise neurons that release the neurotransmitter acetylcholine, which originate in the reticular core of the brainstem and basal forebrain. Enhance the amount of cholinergic activity and this should lead to improvement in the efficiency of working memory.
• At this time, there is no known cure for this disease.
• Anticholinesterase inhibitors may retard the development of cognitive loss in individuals with mid to moderate dementia.
• Alzheimer's disease medicines work to slow down the symptom progression rather than substantially improving memory function.
• The four cholinesterase inhibitors presently being used are tacrine (Cognex, Parke-Davis), donepezil HCP (Aricept. Eisai/Pfizer), rivastigmine (Exelon, Novartis) and. galantami ne hydrobromide (Reminyl, Shire Pharamaceutical and Johnson & Johnson). Tacrine and donepezil are classified as short-acting or reversible agents since when binding to acetylcholinesterase enzyme (AChE) it is hydrolyzed within minutes. Rivastigmine is classified as an intermediate-acting or pseudo-irreversible agent due to its long inhibition on AChE of up to 10 hours.Galantamine also is classified as acetylcholinesterase inhibitor. It also appears to act on nicotine receptors in the brain. Both the acetylcholine and nicotine receptors have been suggested as areas related to cognitive impairment.
• There are free radical scavengers that have been proposed as effective in the treatment of cognitive disorders, but there continues to be questions about their effectiveness. Included in this group is Vitamin E, Selegiline (Eldepryl, Somerset etc.), and extract of Ginkgo biloba.
• Eating nuts, leafy green vegetables and other foods rich in antioxidants such as vitamin E may reduce the risk of Alzheimer's disease according to two recent studies. The studies suggest that vitamin-rich foods-not supplements-impart the beneficial effects. Intake of Vitamin C appeared to offer some protection also, but the results were not as clear cut as were the results for Vitamin E. More definitive studies on this are still required.
• Many drugs are in different clinical trial levels, hoping for approval, since more effective drugs are needed and there is a large cohort group that can use this medication.

See: Alzheimer's Disease Part I-Medications for Alzheimer's.
See: Alzheimer’s Disease Part II- Selegiline and AD.
See: Alzheimer's Disease Part III- Use of Gingko Biloba in memory problems of Alzheimer patients.
See: Alzheimer's Disease PartIV-Alternative Treatment.
See: Alzheimer's Disease Part V-Possible New Drugs for Alzheimer's Disease Treatment.
See: Alzheimer's Part VI -Early Diagnosis.
See: Alzheimer's Part VII -New Medication-Metrifonate
See: Alzheimer's Part VIII-Implications of Longer Life Expectancies
See: Alzheimer's Part IX-Ethical Care Principles
See: Alzheimer's Disease Part X-Estrogen and Alzheimer's Disease
See: Alzheimer's Disease Part XI-Pocket Smell Test
See: Alzheimer's Disease Part XII-MAO-B
See: Alzheimer's Disease Part XIII-Critical Flicker Fusion Threshold Test
See: Alzheimer's Disease Part XIV-Donepezil
See" Alzheimer's Disease Part XV-Cerebroylsin
See: Alzheimer's Disease Part XVI-MCI
See: Alzheimer's Disease Part XVIII-NO Releasing NSAIDs
See: Alzheimer's Disease Part XIX-Vitamin E
See: Alzheimer's Disease-Part XX-Clinical Trials
See: Alzheimer's Disease Part XXI-The Brain
See Dementia with Lewy Bodies- Part XXII-by Gourete Broderick
See: Alzheimer's Disease-Part XXIII-HMG
See: Alzheimer's Disease-Part XXIV-A Prequel
See: Alzheimer's Disease-Part XXV-Psychosis
See: Alzheimer's Disease-Part XXVI-Amyloid-beta Hypothesis Controversy
See: Alzheimer's Disease-Part XXVII- AD and Diabetes
See: Alzhemeir's Disease-Part XXVIII - Insulin and AD

FOR AN INFORMATIVE AND PERSONAL ARTICLE ON PRACTICAL SUGGESTIONS WHEN SELECTING A NURSING HOME SEE OUR ARTICLE "HOW TO SELECT A NURSING HOME"

Harold Rubin, MS, ABD, CRC, Guest Lecturer
updated January 28, 2009

http://www.therubins.com

To e-mail: hrubin12@nyc.rr.com or rubin@brainlink.com

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