There are many possible causes of dementia or the loss of higher intellectual function. The diagnosis must be considered by a highly trained physician, preferably a neurologist. The clinical evaluation must include a medical history and examination, a mental status evaluation and appropriate laboratory tests. Forgetfulness with aging afflicts most of the human race after the age of forty and most often is benign. The differential diagnosis is extensive. Dementia can be induced by medication, systemic illnesses, vitamin deficiencies, such as B12 and folate, hypothyroidism, multiple small strokes, hydrocephalus, subdural hematomata from head trauma and even unsuspected depression. However, the experienced cliniciancan, and should recognize the warning signs of Alzheimer's disease. The following checklist has been published by the Alzheimer's Association of America (4). Although it is non specific, the presence of these symptoms should alert patients and families to the existence of some form of dementia and the need for additional testing for the presence of Alzheimer's disease.

1. Recent memory loss that affects job skills.

2. Difficulty performing familiar tasks like meals.

3. Language problems like word substitutions.

4. Disorientation of time and place, i.e. how to get to a familiar place.

5. Poor or decreased judgment, i.e. dressing inappropriately.

6. Problems with abstract thinking.

7. Misplacing things, i.e. an iron in a refrigerator or a wristwatch in a sugar bowl.

8. Changes in mood or behavior, i.e. rapid mood swings.

9. Personality changes, i.e.confusion, suspicion, unwarranted fear.

10. Loss of initiative, i.e passivity about life.

GENETICS

Although the majority of Alzheimer's patients have a spontaneous onset of the disease, familial forms exist and the study of afflicted families has enhanced our genetic understanding of this form of the disease. One subtype, called AD3, has an early onset between the ages of 28 to 65 years. The gene for this disease subset, Presenilin (PS) 1 gene, has been mapped to chromosome 14. Sequencing of this gene has demonstrated many missense mutations to be present. The course of this disorder is more rapid than the spontaneous form i.e., 8-10 years as compared to 10-15 years for most cases of Alzheimer's Disease. When the PS1 gene was cloned, a second gene, PS2, very similar to PS1 was found on chromosome 1. Interestingly, PS2 gene was described in two pedigree families with somewhat different mutations, one of Italian ancestry and the other of Volga German ancestry. It has been hypothesized that the presence of either PS1 or PS2 genes drives normal precursor proteins in central nervous system cells away from the normal pathways toward the overproduction of an AB peptide which makes amyloid which in turn destroys cell function. Another gene defect, APOE E4 polymorphism, has been found on chromosome 19. Although some controversy still exists about the significance of the presence of this gene defect, it is generally agreed that "those who have two copies of APOE E4 (one from each parent) are at highest risk of getting the disease and are affected at an earlier average age than those with one or no copies of this allele" (5). A fourth gene defect, B APP mutations, has been discovered on chromosome 21. All of the above are implicated in neuronal death and the pathogenesis of this disease. All of these test are abailable to clinicians but their use should be limited to specialists and to those cases of early onset disease with a clear pattern of autosomal dominant inheritance. Their use in asymptomatic members ofa pedigree must be governed by moral and ethical concerns, preferably in a formal genetic counseling program. Athena, a diagnostics company that specializes in the testing of the nervous system has developed useful measurements of cerebrospinal fluid (CSF) markers, tau end AB42. CSF levels of TAU are elevated in Alzheimer's disease patients (6) and AB42 levels are lowered, (7) the latter in patients that are APOE E4 positive. It is thought that the AB42 is decreased in the CSF because it is deposited in the abnormally forming neuritic plaques. NYMOX Corporation has just released AD7C, "The Test" to rule out AD. It is still considered experimental. The genetic discussion above would have been unthinkable just ten years ago.

PHARMACO THERAPY

The CNS neurotransmitter, acetylcholine has consistently been demonstrated to be deficient in AD and thought to be the cause of cognitive impairments(8). Since 1993 a palliative treatment for mild to moderate AD based upon chilinergic enhancement has been available. Tetrahydroaminoacridine (THA), Tacrine, is a cholinesterase inhibitor. It is thought to act by increasing cortical acetylcholine. 120 mgm/day and 160mgm/day doses were found to improve cognitive performance tests as well as physician rated global impressions. Less than a third of patients improved, but some did dramatically. Tacrine's usefulness has been limited by adverse affects, particularly hepatic transaminase elevations. A newer drug, Donepezil, Aricept, is well tolerated and also has been shown to improve cognition and global function in patients with mild to moderate AD (9). At the time of this writing it is the pharmacotherapy of choice. There are several choline enhancing drugs in the pipeline. Metrifonate and ENA-713 (Exelon) are currently in phase III development (10).

TEAM APPROACH

Patients and caregivers need education about what to expect as the disease progresses. Stress management and the treatment of depression in both the patients and caregivers is crucial to the management of this disease which affects entire families. It is crucial to consider the family's values, and their culture in order to best help them through this ordeal which can last more than a decade. Professional organizations like the Alzheimer's Association can be exceptionally helpful in sharing their experience and providing educational materials and social support for AD patients and their families.

THE FUTURE

The next decade promises a better understanding and treatment of this depredating illness. A definite, easy to obtain diagnostic test, genetic markers for prognosis of progression, better pharmacotherapy, nerve growth factors and CNS neuronal replacement by surgical grafts are already on the horizon.

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