Behavioral and psychiatric symptoms of dementia are very common and are often more distressing than consequences of cognitive impairment. These symptoms are associated with increased healthcare use, earlier institutionalization 1. excess morbidity and mortality, greater caregiver distress and depression 2. While the psychiatric symptoms are well defined and use uniform terminology, there is a confusion about terminology of behavioral symptoms. While the group of experts, convened by the International Psychogeriatric Association (IPA) defined agitation as a behavior “manifesting excessive motor activity, verbal aggression, or physical aggression” 3, other authors separate agitation and aggression and consider them as two separate syndromes, which may coexist in one individual but not at the same time 45.

Separation is of aggression and agitation is based on different circumstances present when these syndromes occur and several rating scales, including MDS 3.0 make this distinction 67. Aggression is overt behavior of animals or humans involving intent to harm another organism or inanimate object.8 while agitation may be defined as “Motor restlessness, heightened responsivity to stimuli,irritability, inappropriate and/or purposeless verbal or motor activity, decreased sleep, and fluctuation of symptoms over time.“ 9 that may occur when the person with dementia is solitary and does not interact with others. Although majority of IPA experts decided that aggression is a part of agitation, they did not have any scientific basis for this conclusion. The aim of this paper is to provide information indicating that separation of aggression and agitation is supported by differences in neuroanatomical and neurochemical changes occurring in these two syndromes.

Medline was searched using “dementia AND behavior AND brain changes AND people”. The search identified 811 publications. By reviewing abstracts of these publications, 17 were selected for detailed review of the methods used in the study. In 10 papers, methods used by the investigators clearly differentiated between aggression and agitation and were included in this study. Several scales were used by investigators and Table 1 lists items of these scales which were used to indicate aggression or agitation. It is important to recognize that the names of domains in some scales are confusing. That is especially true for the Neuropsychiatric Inventory (NPI), where item Agitation/Aggression measures resistiveness to care which may escalate to combative behavior and reactive aggression. That item Agitation/Aggression is measuring resistiveness to care is especially clear from description of this item in NPI-NH version (Table 1) and in NPI-Q version where the only question is “Is the patient resistive to help from others at times, or hard to handle?” 1011.

There were several differences in neurobiological substrates found in persons who exhibited agitation and in persons who exhibited aggression. These differences were detected in both clinical and post-mortem studies (Table 2, Table 3)

The confusion regarding terminology of behavioral symptoms of dementia is not new and is perpetuated by the multitude of instruments used to evaluate these symptoms. A recent review evaluated 83 instruments developed to measure behavioral and psychological symptoms of dementia. 23. This review is considering only those instruments that clearly differentiated between agitation and aggression, because only studies using these instruments could differentiate neurobiological substrates of these syndromes.

The first scales, that evaluated neurobiological substrate, were Cohen-Mansfield Agitation Inventory (CMAI) 24 in the United States and Present Behavioral Evaluation (PBE) 6 in the United Kingdom. Both of these scales differentiated agitation and aggression, although CMAI called physical and verbal aggressive behavior “agitation”. Neither of these scales included psychiatric syndromes and this omission was corrected by development of the Neuropsychiatric Inventory (NPI) 25 that included not only behavioral but also psychiatric syndromes . However, there was a problem with this scale because one of the domains of the scale, Agitation/Aggression, combined in its name both of these syndromes, while it measured only reactive aggression resulting from rejection of care. Non-aggressive behavior, that was considered agitation in other scales was evaluated mostly by the domain Aberrant Motor Behavior.

Several efforts were made to simplify the response structure of NPI but they usually resulted in emphasizing psychiatric conditions instead of differentiating behavioral symptoms 26. For instance, the Cache county study identified only three clusters: an affective syndrome, a psychotic syndrome and other neuropsychiatric disturbance 27. The most recent factor analysis of NPI identified four subsyndromes: Hyperactivity, Psychosis, Affective, and Apathy. However, Aberrant Motor Behavior was included in three of these subsyndromes depending on the type of dementia 28. More recently, NPI-C Research Group 29 designed new version of NPI that includes expanded domains, more items, and a clinician-rating methodology. This version separated Agitation and Aggression into two domains. Unfortunately, the probing question for agitation remained the same as in the original NPI “Is (S) hard to handle or uncooperative or resistive to care?” and thus this domain evaluates presence or absence of rejection of care which has nothing to do with agitation.

Despite this acknowledgement that agitation and aggression are two separate syndromes, a group of experts, convened by the International Psychogeriatric Association (IPA), developed provisional consensus stating that agitation is manifested by excessive motor activity, verbal aggression, or physical aggression 3. Separation of agitation and aggression is complicated by the fact that both of these syndromes can occur in the same person 4. However, they may not occur at same time, and this fact is not captured by the current scales relying in proxy reports, because these reports usually concern behaviors occurring during the past few weeks. It is hoped that evidence of differences in neurobiological substrates between agitation and aggression, presented in this paper, will be taken into consideration for possible revision of agitation definition.

Distinction between agitation and aggression is important for both non-pharmacological and pharmacological management of behavioral symptoms of dementia. Non-pharmacological strategies used for treatment of agitation need to concentrate on providing meaningful activities because agitation is often caused by boredom of persons with dementia 30. In contrast, aggression is in most cases reactive aggression elicited by rejection of care. Therefore, its management should concentrate on improving communication and on changing care strategies to prevent escalation of rejection of care into combative behavior and reactive aggression 31. Although drug studies were not specifically designed to evaluate effects on specific syndromes, there is some indication that medications affect differentially agitation and aggression. Antipsychotics seems to be more effective in treatment of aggression 32 and risperidone is actually indicated for treatment of ” persistent aggression in patients with moderate to severe Alzheimer’s dementia” by the European Medicines Agency 33. In contrast, donepezil was found to improve only non-aggressive behaviors 34.

There is a danger that a medication may be developed and approved by the FDA with indication of agitation without recognizing the difference between agitation and aggression. It is important to realize that Minimum Data Set 3.0 does not contain the term agitation. It is distinguishing behavioral symptoms, according to the involvement of others, into behaviors directed towards others and behaviors not directed towards others. Aggression by definition involves others, while damaging equipment may be just an escalation of agitation (e.g., damaging a chair by restlessness), not directed toward others and not real aggression. Providers of care for persons with dementia need a clear connection between their evaluations and research results, and a confusing concept of agitation that includes aggression is not going to help the in providing appropriate care for persons with dementia who exhibit behavioral symptoms.

There are some limitations of this study. The main one is that there is not enough information available to construct a mechanism underlying neurobiological mechanisms related to agitation and aggression. Therefore, this paper is limited to pointing out that the neurobiological indices are differentiating these two syndromes. The second limitation is the use of results obtained with scales that rely on proxy reports. These scales do not provide information about the context in which these behaviors occurred. Thus, the same person may be considered to exhibit both agitation and aggression, but these behaviors may occur in different times and different contexts. However, despite these limitations, data presented in this review indicate that agitation and aggression should be considered as two independent syndromes. The third limitation is that subjects involved in these studies had several causes of dementia. However, large-scale studies showed no difference in the prevalence of neuropsychiatric behaviors between Alzheimer's disease and non-Alzheimer's disease dementias 35 and another study concluded that neuropsychiatric subsyndromes are consistent across dementia subtypes, age and gender 28. Although the reviewed studies do not provide enough information about neurobiological changes in specific dementia subtypes, it is possible to suggest that agitation and aggression are two different syndromes in all subjects with dementia.