Neurobiological Differences Between Aggression and Agitation in Persons with Dementia

Abstract Background Controversy exists about definition of agitation and especially about inclusion of aggression as a part of agitation in people with dementia. Methods Papers describing neurobiological indices related to behavioral symptoms of dementia were reviewed. Papers comparing indices in persons exhibiting aggression and persons exhibiting agitation were selected for this review. Results The survey found seven papers which compared neuroanatomical indices and three papers which compared neurochemical indices. The neuroanatomical indices differentiating agitation and aggression included changes in brain perfusion, sizes of brain areas, distribution of neurofibrillary tangles, and white matter changes. The neurochemical indices differentiating agitation and aggression included relationships with neurotransmitter variables and the cell count in the locus coeruleus. Conclusion Despite the small number of papers and some methodological problems, the presented information clearly indicates that aggression and agitation are two distinct unrelated syndromes in persons with dementia. DOI: 10.14302/issn.2470-5020.jnrt-18-2554


Introduction
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 [4,5].

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 [6,7].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.

Methods
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  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?" [10,11].

Results
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)

Clinical Studies
Differences between aggression and agitation included changes in brain perfusion, differences in brain atrophy, and white matter changes.Hirono et al [12] compared the pattern of regional cerebral Caretaker obstreperous-behavior rating assessment (COBRA) scale 41   Resistiveness to Care -Dementia of the Alzheimer Type (RTC-DAT) scale 42

Post-Mortem Studies
Two studies reported increased load of neurofibrillary tangles (NFTs) in aggressive subjects with dementia.Lai et al [17]

Discussion
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]  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.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.

4 -
examined hippocampi of 27 subjects who had premortal evaluation of their behaviors by the Present Beavioral Evaluation (PBE).Of the 27 patients, 21 were neuropathologically confirmed to have Alzheimer's disease whereas three patients were determined to have vascular dementia.One patient had mixed vascular dementia and Alzheimer's disease, another had an unusual tauopathy, and one had nigral cell loss and evidence of ischaemic hippocampal damage.Using factor analyses of the point of entry interview data, three component behaviours have been identified for aggression (physical aggression, verbal aggression, aggressive resistance to intimate care) and overactivity (walking more, aimless walking, trailing and checking) syndromes.The investigators found that neurofibrillary tangles were significantly elevated in subjects with history of aggressive behavior while there was no difference in neurofibrillary tangle density in subject with and without chronic overactivity.Tekin et al [18] examined postmortem brain of 31 subjects with diagnosis of AD, who had NPI evaluation before death.They found that Agitation/ Aggression item was related to NFT burden in the left orbitofrontal cortex and left anterior cingulate, while Aberrant Motor Behaviors showed a significant relationship with NFT density only in the left orbitofrontal cortex.There are several neurotransmitters that are affected differently by aggression and agitation.Garcia-Alloza et al [19] examined post-mortem brains of 22 patients with clinical diagnosis of dementia and 20 elderly normal controls matched for age, gender, post-mortem delay and brain pH, who were evaluated by the PBE before death.Their results showed that aggressive behavior scores were the best predictors of lowered choline acetyltransferase (ChAT) and acetylcholine esterase (AChE) levels in both frontal and temporal cortices, while overactivity factor was the best predictor of serotonin (5-HT) reductions in the frontal cortex.Vermeiren et al [20] did an extensive study measuring concentrations of dopamine, 5-HT, norepinephrine, and respective metabolites using reversed-phase high performance liquid chromatography in brains of 40 neuropathologically confirmed AD patientsdihydroxyphenylacetic acid (DOPAC)/dopamine ratio, but no relationship between any neurotransmitter values and aggressive behavior.The same investigators found some correlation between neurotransmitter values and aggressive behavior in another paper, but in that study they compare only aggressive and non-aggressive subjects and did not include subjects with non-aggressive behavior as a separate group [21].Differential involvement of the noradrenergic system is suggested by cell count in the locus coeruleus.Matthews et al [22] studied post-mortem brains of 46 individuals with a clinical diagnosis of dementia and 33 elderly normal control cases.The dementia individuals included 36 subjects with AD and 10 subjects with mixed dementia.All had pre-mortem longitudinal evaluation of their behavior using PBE scale.The investigators found that there was a strong correlation between the mean cell count at level A of the locus coeruleus and the presence of aggressive behavior during the illness, with lower cell counts being associated with an increased severity of aggressive behavior.There was no relationship between overactivity and cell count.

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 Neuropsychiatric Inventory (NPI), where item Agitation/ Aggression measures resistiveness to care which may escalate to combative behavior and reactive aggression.

Table 2 .
Neurobiological indices related to aggression and agitation 38Behaviour resulting in or liable to result in actual physical harm to another person Walking more, aimless walking, and trailing and checking Table 1.Definitions of aggression and agitation by the scales used in this review www.openaccesspub.org| JNRT CC-license DOI : 10.14302/issn.2470-5020.jnrt-18-2554Vol-2 Issue 4 Pg.no.-31