Diagnosing Ad

of the patient's symptoms. Preliminary diagnosis of AD revolves around assessment of hippocampus-dependent memory function, for the most part. For example, a typical test battery involves giving a list of three words and then asking the patient to recall them at some later point in the interview (see reference 79). The general degree of orientation and attention on the part of the patient are also evaluated. A commonly utilized test battery is the "Mini Mental State" battery, which evaluates orientation, memory, concentration, and language usage (80). A slightly more detailed exam is the "Blessed" battery, also known as the Information-Memory-Concentration Test (81), performance on which has been correlated with post-mortem assessments in the same individual.

A thorough neurological exam is also requisite as part of the diagnostic process because diagnosis of AD is, in large part, an elimination of other possible explanations— a diagnosis by serial elimination. Other possibilities that need to be excluded are stroke, trauma, diffuse vascular insult, transient delirium due to metabolic imbalance, Parkinson's disease, psychosis, and "pseudodementia" associated with depression. Brain imaging is a necessary adjunct to assess specific anatomical pathologies such as tumors and strokes. Although brain imaging techniques do not allow independent diagnosis of AD, specific metabolic changes in the temporal lobes associated with AD can be detected with PET scans (see reference 82).

The state of the art in diagnosing AD is steadily improving. The rapid expansion of our understanding of the genetic components contributing to AD will no doubt allow further refinements in pre-mortem diagnosis of AD. The irony of the present situation is that because no effective treatments for AD pathogenesis are available at present (see Box 2), a definitive diagnosis of AD is of little direct benefit to the patient. This might lead one to ask the question, "What's the point?" If nothing else, it helps the patient and their families prepare for what lies ahead. However, there also is a larger picture to be kept in mind. There are many ongoing clinical trials related to various aspects of AD, including trials related to the development of new AD treatments. Patients diagnosed with AD potentially will benefit themselves by participating in these trials, and definitely through their participation the greater society in which we all live will benefit. Diagnosis opens the door for this opportunity.

ongoing discoveries of the cellular and molecular basis of hippocampal function in order to improve our understanding of the earliest stages of AD. For the rest of the chapter, I will proceed with this perspective in mind—biasing the discussion toward early molecular events of relevance to the hippocampus and hippocampal synaptic plasticity.

B. Pathological Hallmarks of AD

It has been known for almost a century now (10) that AD clinical signs and symptoms are correlated with selective dysfunction (and ultimately death) of neurons in brain regions and neural circuits critical for memory and cognition (see Table 1). These include the hippocampus, amygdala, neocortex, anterior thalamus, the basal forebrain cholinergic system (see Box 2) and the mono-aminergic brain stem system (6, 11-15). Areas initially affected are the entorhinal and transentorhinal cortex, and parts of the hippocampus. This progresses to increasing hippocampal involvement and is followed by spread to the amygdala and limbic nuclei of the thalamus. It is accompanied by a worsening of initially affected areas. Final stages involve various areas of the cerebral cortex with subsequent cellular pathology in the association areas.

At the cellular level, a predictable sequence of damage to these brain regions occurs. A principal pathologic feature of AD brain are the presence of senile plaques

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