INTRODUCTION

Alzheimer’s disease is a progressive degenerative disorder of insidious onset, characterized by memory loss, confusion, and a variety of cognitive disabilities. It is the major cause of dementia in the elderly and is characterized by the presence of neuropathologic lesions including: neurofibrillary tangles in the neuronal perikarya and in pyramidal neurons of the hippocampus, entorhinal cortex and neocortex, nucleus basalis of Meynert, and periaqueductal gray. Neuritic (senile) plaques often with a central or core deposition of amyloid within the plaque and in some cases with amyloid infiltration of blood vessel walls (amyloid angiopathy) and the adjacent perivascular neuropil; loss of neurons, most often in the hippocampus, neocortex, locus coeruleus, and nucleus basalis; and disturbance of acetylcholine transmitter activity marked by lowered levels of acetylcholine and choline acetyltransferase (4).

ETIOLOGY

Alzheimer’s disease may strike as early as age 40, but is most common after the age of 60. As the average life expectancy continues to increase so too does the incidence of AD. In its early stages it is difficult to distinguish from normal aging. However, whether AD is a specific qualitative disorder such as an infectious process, endogenous or exogenous toxic disorder or biochemical deficiency, or whether it is a quantitative disorder, in which an acceleration of the normal aging processes occur and dementia appears as neural reserves are exhausted, remains to be seen. New techniques of molecular genetics provide a promising new approach for understanding AD in view of the evidence that there is a familiar factor present in the disease (4). In several studies, over one third of patients with AD have proved to have one or more affected first degree relatives. As it stands, however, the cause of AD remains unknown.

DIAGNOSIS

Unfortunately the most accurate diagnosis of Alzheimer’s disease is by postmortem examination of the brain. The disease itself is not well defined, and its varied yet subtle manifestations lend difficulty in distinguishing it from other nervous system diseases or dementia-causing diseases. The danger exists that appropriate therapy that might bring relief or even cure, might be withheld from some patients if their conditions are misdiagnosed. Because, even though no effective treatment for AD is available, there are useful therapies for various diseases that produce symptoms of dementia (4).

The fact that AD usually develops later in life again complicates the boundaries of this disease. Because the process of normal aging is not completely understood, there are no consistent, established values of what constitutes "normal" cognitive impairment and memory loss with advancing years. Furthermore, the neurochemical changes, the neurophysiological changes, or the gross and fine anatomical changes that accompany normal aging are not understood well enough to provide a firm basis for determining "abnormal" changes. The brain of an 80 year old patient with AD may be difficult to distinguish from that of an age-matched normal patient without dementia. Also, some elderly patients have few or no senile plaques or neurofibrillary tangles. Even at earlier ages, the neurofibrillary tangles and senile plaques that characterize the brain with AD may also appear in normal brain, although in smaller quantities. Determining the definitive pathologic lesions of AD on the basis of counts of tangles and plaques lends itself to controversy. A better understanding of the normal aging process will undoubtedly aid in the accurate diagnosis of Alzheimer’s disease.

DISCUSSION

A basic hallmark of AD is the loss of cholinergic neurons that result in a lowered level of acetylcholine and of an enzyme necessary for its synthesis, choline acetyltransferase (ChAT). Cerebrospinal fluid may be the source of a useful marker for levels of ChAT in suspected patients with AD. ChAT levels seem to be progressively lowered in CSF as cholinergic neurons die in the course of the disease (other transmitter systems and peptides are also affected in AD—noradrenaline, dopamine, somatostatin, substance P).

The effect of age upon the cholinergic innervation of the cerebral cortex has attracted considerable attention; however, not all reports are in agreement regarding the depletion of cholinergic markers in the course of normal aging. Substantial reductions in the ChAT activity in the Alzheimer’s disease cases has been a common theme in recent articles, and it has been shown that these cortical ChAT levels decrease with increasing numbers of neuritic plaques (2). A number of studies have compared age-related changes in density of cholinergic fibers with those in AD - a disease which is known to be accompanied by a marked depletion of cortical cholinergic innervation (1). A brief review of these follows: Cholinergic innervation is widely distributed in the cerebral cortex of the mammalian brain and displays regional variation. The level of cholinergic markers is highest in limbic and paralimbic areas (entorhinal and cingulate), lowest in fronto-temporo-parietal association areas. The basal forebrain appears to be the exclusive origin of this cholinergic innervation.

In a study comparing six normal brains from individuals 22-91 years of age (group A) with no prior dementia, and six brains from individuals with clinical history of dementia of the Alzheimer type (group B), three major findings were revealed:

1) The existence of regional and laminar variations in the density of cortical cholinergic fibers.
2) A modest age-related decline in this innervation.
3) A dramatic and regionally selective decrement of cholinergic innervation in AD.

A number of studies have indicated the relative stability of striatal cholinergic markers and neurons in aging and Alzheimer’s disease. Brain tissue from 10 normal subjects (ranging in age from 3 weeks to 91 years) and 4 patients with clinical histories of dementia (ranging in age from 76 to 89 years). The sample was divided into 4 groups: pre-adult, young adult, old adult, and AD. Plaques and tangle concentrations consistent with the diagnosis of AD were found only in patients with a history of dementia. Striatal cholinergic neurons were visualized Immunohistochemically using polyclonal antibody, and numerous ChAT-positive neurons were detected in the caudate and putamen of all subjects. Comparison of average cross-sectional area of ChAT-positive cells in the young adult and the old adult groups showed no significant age-related changes in the caudate nucleus or the putamen. In addition, no significant differences were noticeable in these cells in the subjects with AD as compared to the old group. Therefore, no changes in the density of striatal ChAT-positive neurons as a result of normal aging or AD were revealed. Finally, the pathological process in AD does not seem to influence the size of these neurons in sharp contrast to the cholinergic cells of the basal forebrain which have been shown to undergo considerable depletion and atrophy in AD (2).

In a study of 28 demented in-patients, evaluated levels of CSF seemed to indicate that low levels of ACTH are typical of dementia. The 28 patients showed a significant decrease in ACTH as compared with controls. A CT scan evaluation found 20 out of 28 patients showed pathological cortical index and their ACTH levels were much lower than those of non-atrophic subjects. It is known that ACTH and it’s N-terminal fragment show positive effects on different learning and memory tasks. ACTH 4-9 administered sub-chronically to elderly patients improved mood, sociability and ward behavior (3).

With advanced age moderate changes in learning and memory capacity have been reported. So too is the case in AD. With the body of evidence demonstrating the influence of the cholinergic system on these functions, it is highly possible that the modest loss of cortical cholinergic innervation in the elderly could be in part responsible for the cognitive deficits. Furthermore, loss of cortical cholinergic innervation may also be the reason for other behavioral changes seen in AD (1). It is obvious that sorting out the presence of overlapping symptoms makes it difficult for effective diagnosis and treatment. To complicate the issue even further, other diseases can be confused with AD including pick’s disease , multi-infarct dementia, and other forms of cerebrovascular disease, Parkinson’s disease, hydrocephalus, amyotrophic lateral and multiple sclerosis, and dementia’s resulting from tumors and brain injuries. In light of all this, with an aging population, it is clear to see the need for further study in order to gain a better understanding of the cause and parameters of AD.

BIBLIOGRAPHY:

1) Guela and M. Mesulam (1989). Cortical Cholinergic Fibers in Aging and Alzheimer’s Disease: A Morphometric Study. Neuroscience, Vol.33, No.3: pp. 469-481.

2.)Guela, C., Tokuno, H., Hersh, L., and Mesulam, M., (1990). Human Striatal Cholinergic Neurons In Development, Aging and Alzheimer’s Disease. Brain Research, 508: pp.310-312.

3.) Nappi, G., Sinforiani, E., Martigonoi, E., Petraglia, F., Rossi, F., Genazzani, A. R. (1988). Aging Brain and Dementia’s: Changes in Central Opioids. European Neurology. 28: pp.217-220.