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Dementia affects at least 10% of patients older than 60 years and more than a third of patients older than 80 years. It is estimated that, by the year 2030, 14 million Americans will have Alzheimer's disease (AD), the most common disease underlying late-life dementia and the leading cause of nursing home placement in the elderly.

Neuropsychiatric behavioral symptoms are frequent in patients with dementia. It is estimated that between 61% and 92% of patients with AD will develop disruptive agitation during the course of their illness. Agitation is characterized by excessive verbal and motor behaviors, which suggest that the patient is distressed. Disruptive agitation includes such behaviors as hitting, biting, screaming, constant requests for attention, repetitive vocalizations, verbal threats, and forced motor activity like pacing. In 20% to 30% of cases, agitation is accompanied by psychotic symptoms such as hallucinations and delusions.

Agitation adversely affects quality of life for both the patient and the caregiver. More than 70% of caregivers consider the management of disruptive agitated behaviors to be the most challenging aspect of the caretaking process. Along with sleep disturbances, it is the major precipitant of institutionalization. In the nursing home setting, the management of agitation requires a high caretaker-to-patient ratio, further increasing the public health burden of this costly disease, which is presently estimated at $100 billion per year.

The effects of AD on brain function and a number of neurotransmitters may contribute to the pathophysiology of neuropsychiatric behavioral symptoms in AD. In a fluorodeoxyglucose-positron emission tomography study mapping psychosis in AD, hypometabolism in the right prefrontal cortex was associated with delusions. Single photon emission computed tomography studies in patients with AD, with aggressive behaviors, demonstrated abnormalities in the right anterior medial temporal region.

Changes in a number of neurotransmitter systems likely contribute to the pathophysiology of agitation in AD. There is severe loss of cholinergic neurons in the basal forebrain nucleus basalis of Meynert and reductions in choline acetyltransferase (the synthetic enzyme for acetylcholine with a corresponding cholinergic deficit). In large clinical trials of acetylcholinesterase inhibitors (AChEIs; drugs that inhibit the enzymatic breakdown of acetylcholine and act to ameliorate the cholinergic deficit), there was a decreased incidence of emergent behavior problems in mild–moderate AD and a reduction in these behaviors in moderate–severe AD. These findings suggest that a subsyndromal “anticholinergic delirium” may contribute to the development of neuropsychiatric behavioral symptoms in AD. A caveat is that persons with severe disruptive agitated behaviors were excluded from trials of AChEIs. The role of AChEIs in the treatment of disruptive agitated behaviors is discussed below.

Loss of serotonergic neurons in the dorsal raphe nuclei results in a deficit state, which may be associated with depressive symptoms, irritability, and anxiety. Loss of dopaminergic neurons in the substantia nigra is variable, but there is little evidence for loss of dopaminergic function in AD.

Despite severe loss of neurons in AD ...

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