Alzheimer’s disease Paul R. Earl Facultad de Ciencias Biológicas Universidad Autónoma de Nuevo León San Nicolás, NL, Mex

1. Alzheimer’s diseasePaul R. EarlFacultad de Ciencias BiológicasUniversidad Autónoma de Nuevo LeónSan Nicolás, NL, Mexico

2. A German doctor Alois Alzheimer (1864-1915) in 1907 published on a degenerative attack on the nerve cells of the cerebral cortex—a brain disorder—in Z Psychiatrie Psychisch-Gerichtlich Medizine 64: 146-148 that became known as Alzheimer’s disease (AD). Possibly 5 million people over 65 have AD in the US, and the number of AD cases may triple by 2050. It is a progressive disease of the brain that is characterized by loss of memory and a disturbance in at least one other thinking function (for example, language or perception of reality). Loss of nerve cells in strategic brain areas, in turn, causes deficits in the neurotransmitters, which are the brain’s chemical messengers—mainly acetylcholine.

3. AD’s gradual, yet relentless attack on memory is the major sign and the earliest. Symptoms extend to other cognitive deficits in language, object recognition and executive functioning. Psychosis, agitation, depression and wandering—are common. Incidentally, the German word for madness is DerWandersinn. AD is a neurodegenerative disease that begins with an insidious and progressive course and great clinical variability, ending by 10 years. Alois Alzheimer

4. A reduced amount of acetylcholine is thought to cause the loss of memory. Reduced cerebral blood flow might also be involved in AD. Nevertheless, amyloid disequilibria with plaque formation and the death of neurons seem still more important as causes of dementia and death. The other causes of dementia that must be ruled out include cerebrovascular, Parkinson’s and Huntington’s diseases, subdural hematoma, normal-pressure hydrocephalus, brain tumor and systemic conditions, e.g., hypothyroidism, vitamin B12 & E, folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection and toxicities. The factors of diseases can be summarized as: 1/ too little, 2/ too much or 3/ the wrong kind.

5. The key to dementia is age (??) !Alzheimer’s disease, remote from normal ageing, is the most prevalent form of dementia, and billions of dollars in costs that are rising as the elderly population proportionally takes up more of the population. Regardless, many of the issues raised also pertain to other forms of dementia such as multiinfarct dementia, dementia of Parkinson’s disease, dementia of Huntington’s disease, dementia of Pick’s disease, frontal lobe dementia and others.Apathy is a major feature of both depression and AD.

6. Symptoms in AD might be:1/ Apathy, 2/ Wandering, 3/ Depression, 4/ Aggression, 5/ Delerium, 6/ Hallucination and 7/ Mania. Over 90 years of age means over 30 % AD and possibly 50 %.The public views forgetfulness or "senility" as a normal part of aging, and this is not so.

7. Sometimes AD is a Family DiseaseGenetic factors appear to play a significant role in the pathogenesis of Alzheimer’s disease. In its familial form, AD is caused by mutations in chromosomes 1, 14 & 21, and 1 and is transmitted in an autosomal dominant mode. Each of these mutations appears results in the overproduction of the B amyloid protein found in neuritic plaques. Onset of the familial form is usually early. However, the familial form accounts for less than 5 % of AD.

8. Treatment notesThe primary goals of treatment are to improve quality of life and maximize functional performance by enhancing cognition mood and behavior. The expensive hardship is the loss of independence so that the patient at some point with need nursing care. Appropriate drugs that are mainly cholinesterase inhibitors can keep the patient funtional longer.

9. AD begins slowly. At first, the only symptom may be mild forgetfulness,which can be confused with agerelated memory change. Most people with mild forgetfulness do not have AD. In the early stage of AD, people may have trouble remembering recent events, activities, or the names of familiar people or things. They may not be able to solve simple math problems. These difficulties are often not serious enough to cause alarm. Although early and late stage AD could even be different diseases, the constellation of symptoms, age differences at the onset of AD and so forth are not sufficiently clear. Research funding, especially in the third world, for AD is poor. Additional tests including of course genetic ones may allow better estimates of rate of decline.

10. Cholinesterase inhibitors improve central cholinergic neurotransmission. Take Donepezil as an example. It produces improved cognitive effects, e. g., enchanced memory, orientation, language and reasoning over periods of 12-24 weeks without hepatotoxicity. The recommended starting dose of 5 mg/day, increased to 10 mg/day after 1 month. The higher dose, while more efficacious, has a greater tendency to cause cholinergic adverse effects, e. g., nausea, diarrhea and insomnia if increased too rapidly, and such effects may worsen behavior.

11. The fifth approved medication, known as Namenda, Axura and Ebixa (memantine), is an N-methyl D-aspartate (NMDA) antagonist for the treatment of moderate to severe AD. The medication may allow patients to maintain daily functions a little longer. For example, Memantine may help a patient in the later stages of AD maintain his or her ability to go to the bathroom independently for several more months, a benefit for both patients and caregivers. Memantine is believed to work by regulating glutamate, another important brain chemical that, when produced in excessive amounts, may lead to brain cell death.

12. DRUG NAMESNamenda (memantine). Blocks the toxic effects associated with excess glutamate and regulates glutamate EFFECTS include activation.Reminyl (galantamine). Prevents the breakdown of acetylcholine and stimulates nicotinic receptors to release more acetylcholine in the brain.Exelon (rivastigmine). Prevents the breakdown of acetylcholine and butyrylcholine (a brain chemical similar to acetylcholine) in the brain.Aricept (donepezil). Prevents the breakdown of acetylcholine in the brain.

13. Dementia With Lewy BodiesDementia with Lewy bodies (LB) is the second most frequent cause of degen-erative dementia in elderly adults. LBD is a neurodegenerative disorder associated with abnormal structures found in the brain sometimes associated with Parkinson’s disease and AD. LB contain deposits of the protein alpha-synuclein that is also linked to Parkinson’s disease and multiple system atrophy. Symptoms can range from traditional Parkinsonian effects, such as loss of spontaneous movement (bradykinesia), rigidity (muscles feel stiff and resist movement), tremor and shuffling gait to effects similar to those of AD such as acute confusion, loss of memory, and some loss of cognition.

14. How prevalent is AD ?AD affects an estimated 4 million people in the US. It causes anguish to millions more caregivers and family members, who must cope with the patient’s steady irreversible decline in cognition, functioning and behavior. AD might reach 14 million by the year 2040. Patients and caregivers often mistake early symptoms for normal aging changes, and physicians may fail to recognize the initial signs of dementia or misdiagnose them. Regardless, AD and aging are not similar. For example, the cognitive changes of aging as a slowing of information processing are benign, while dementia is progressive and disabling.

15. What is the impact on society ?When the costs of medical and longterm care, home care and lost productivity for caregivers are totaled, the direct dollar expenditure and indirect costs like family care approach $100 billion each year. Medicare, Medicaid and private insurance bear much of the direct cost, but families who care for patients assume the largest portion of expenses.

16. An amyloid plaque stained with Congo Red on the left and neorofibrillary protein on the right.

17. What are the different forms of dementia and how can they be recognized ?AD lasts about 10 years with a range of 3-20. Memory impairment is present in the earliest stages. Patients have difficulty learning and retaining new information. Older memories are lost. Aphasia, apraxia, disorientation, visuospatial dysfunction, and impaired judgment and executive functioning set in. Functional impairment like getting lost occur.

18. The presence of delirium or depression may confound dementia recognition. Delirium is an acquired impairment of attention, alertness and perception. Like dementia, delirium is characterized by cognitive impairment. It can be distinguished by its acute onset, marked fluctuations in cognitive impairment over the course of a day, disruptions in consciousness and attention, and alterations in the sleep cycle. Hallucinations and visual illusions are common. A general medical condition, such as infection or metabolic disturbance or drug side effects typically causes delirium. Delirium and dementia often coexist, particularly in a hospital setting. Also, dementia is a risk factor for delirium.

19. Three tests will greatly aid in discriminating the status of the patient. They are: 1/ Measurement of functional activities in older adults in the community. J Gerontol 1982, 37: 323-329, 2/ Assessment of behavioral problems in dementia: The revised memory and behavior problems checklist. Psychol Aging 1992, 7: 622-631 and 3/ ‘Mini-Mental State’: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975, 12: 189-198. See also: Accuracy of clinical diagnosis of Alzheimer disease and clinical features of patients with non-Alzheimer neuropathology. Alzheimer Dis Assoc Disord. 1996, 10: 180-188.

20. HistopathologyHistopathologic changes include neuritic plaques, neurofibrillary tangles, synaptic loss, hippocampal granulovacuolar degeneration and B amyloid angiopathy. ß-amyloid deposition and neurofibrillary tangle formation are two histopathologic features of Alzheimer disease. Most of the genetic risk factors are related to ß- amyloid. Thus, the generation of ß-amyloid peptide is increasingly regarded as the AD central pathologic event.

21. Apolipoprotein E (ApoE) as a major genetic risk factor in AD. ApoE is a normal protein, which transports cholesterol in the circulatory system (www.alzheimers.org). There are three versions of the ApoE gene: ApoE2, ApoE3 and ApoE4. Every person inherits one version of the gene from each parent, and ApoE3 is the most common gene of the three and found in more than half of the population.See http://amyloid.bu.edu/amyloid/Amyloid1.htm which is the Boston University Amyloid Treatment and Research Program.

22. Older Americans ActThe Older Americans Act was originally signed into law by President Johnson in July 14, 1965 (PDF). In addition to creating the Administration on Aging, it authorized grants to States for community planning and services programs, as well as for research, demonstration and training projects in the field of aging. Later amendments as in to the Act added grants to Area Agencies on Aging for local needs identification, planning and funding of services, including but not limited to nutrition programs in the community as well as for those who are homebound. Programs are to serve Native American elders.

23. What successful management strategies are available ?Successful patient management aims to minimize behavioral disturbances, maxi-mize functioning and independence, and foster a safe and secure environment. Several principles are recommended:1/ Schedule regular patient surveillance and health maintenance visits every 3 to 6 months. Evaluate medications periodically, and consider initiating drug-free periods. Check for sleep disturbances and provide guidance on proper sleephygiene. Medicate only as a last resort.

24. What specialized staff and facilities are available to the community ?Geriatricians, geriatric psychiatrists, psychologists, or neurologists should be consulted when the presentation or history is atypical or complex, especially when cases are younger than 60 years. Geriatric psychiatrists and psychologists can provide behavioral management, especially for agitation, psychosis or violent behavior. Management of suicidal behavior or treatment of major depression, and individual or family therapy for patients and caregivers deserves attention. Functional evaluation to make a determination about institutionalization or hospitalization may be crucial.

25. Several specialized services are available in the US, including adult day care and respite care. Skilled nursing care provided by the home health agencies. Help lines of the Alzheimer's Association and outreach services, as offered by area agencies on aging and councils on aging, agencies mandated and funded under the federal Older Americans Act. Aging services also can recommend handypersons and homemakers, friendly visitor or companion programs, and housing and legal assistance. Meals-on-wheels arranges food services for the homebound, while senior citizens centers, church and community groups, and hospitals offer transportation options.

26. What are the most promising research areas ?What barriers contribute to the delivery of inadequate or untimely medical services in primary care settings?Areas of investigation might include the following:1/ physician knowledge about diagnosis and treatment, and the skills required to assess patients;2/ attitudes and beliefs about dementia held by the public and medical professionals;3/ fiscal barriers, including access, insurance coverage, and reimbursement and managed care issues;4/ demographic and socioeconomic factors, including race, ethnicity, and culture;5/ disease complexity and the dependence on specialists to diagnose and treat.

27. How do different health delivery systems influence the course of illness, care settings and impact on the family? How do different disease management models--for instance, primary care vs specialist vs collaborative; psychiatric vs medical; managed care vs fee-for-service--affect diagnosis, treatment and outcome? Which quality indicators are most useful? What are the best ways to maintain the safety and independence of AD patients? When should patients stop driving, living alone or participating in other potentially hazardous activities? What level of care is appropriate and humane for patients with severe end-stage AD? In light of any advance directives that terminal patients may have prepared, is symptomatic treatment warranted? Should life be extended and, if so, for how long?

28. Whenever possible, health services and outcomes research should be conducted in diverse community populations. Most studies of dementia to date have been conducted in academic or other unrepresentative settings. Differences in the quality and level of care in diverse geographic regions and populations and subgroups should be studied. Minorities in particular face very different treatment and management issues. The use of "natural populations" in controlled community settings offers more practical answers to these questions.