Disruptive behavioral symptoms were extremely common in this study; more than 80% of patients with AD manifested them at some point during follow-up. More importantly, DBSs predicted cognitive and functional decline and were associated with a higher risk of institutionalization, even after adjusting for multiple potential confounders. Although our data should provide power to detect mortality prediction effects similar in magnitude to the ones detected for the other outcomes (HR as small as 1.45 according to calculations using baseline DBS), we detected no association between disruptive behavior and mortality.
We found a notable discrepancy between the frequency of DBSs between the first and all subsequent evaluations: fewer than 60% of patients who had such symptoms at some point during the follow-up had them at the first visit. These results likely relate to an increasing prevalence of these symptoms during the course of disease and to the well-described fluctuation of these symptoms from visit to visit.5,7
Therefore, our assessment of these symptoms at multiple visits rather than the usual approach of considering them only at baseline could be a major explanation for discrepancies in findings on the predictive value of these symptoms.
We confirmed the associations between DBSs and the risks of cognitive decline,1,10–15
noted by previous studies. Nevertheless, our results are in discordance with some previous work that failed to detect significant associations between disruptive behavior and cognition,2,16
As in previous studies, agitation/restlessness was predictive of cognitive1,10–15
and functional decline2,15–19
outcomes. In accordance with previous reports, wandering was a significant predictor of functional decline but also the major predictor of institutionalization.10
The association between DBSs and the above outcomes persisted despite controlling for medication effects. Survival in our study was similar to that in a recent report that included patients with AD of similar severity at enrollment.35
Similar to some reports,2
but unlike others,20
we detected no significant association between disruptive behavior and survival.
In the subsample of patients who underwent autopsy, we detected no associations between DBSs and coexistence (in addition to AD) of a pathological diagnosis of Lewy body dementia. The underlying neurobiological process of disruptive behavior is far from clear and has been attributed to alterations in multiple neurotransmitter systems.36
Regarding the adrenergic system, it has been shown that patients with AD who display aggressive behaviors have a markedly higher level of α2
, and β2
adrenergic receptors in the cerebellar cortex.37
There is also a relative preservation of inhibitory noradrenergic neuronal input to the cerebellar cortex (tyrosine hydroxylase–positive neuronal fibers) in patients with AD who exhibit aggressive behavior.38
Regarding the serotoninergic system, loss of serotonin2
) receptors in multiple cortical areas39
and reduced density of 5-HT1A
receptors in temporal areas40
has been reported for patients with AD who manifest aggressive behavior. Decreased 5-HT receptors and 5-hydroxyindoleacetic acid levels in multiple cortical areas for aggressive patients with AD were reported in another study.41
Possible involvement of the serotonin system in DBSs among patients with AD is also evidenced by a series of pharmacotherapy studies.36,42
Regarding the dopaminergic system, according to one report,43
patients with AD and a history of unequivocal interpersonal violence had significantly greater neuron counts in the substantia nigra pars compacta than did nonviolent patients with AD. According to another study,44
DBSs in patients with AD were associated with polymorphisms in the dopamine receptor genes: aggression was significantly more frequent in patients homozygous for the B2 genotype (B2/B2) of the DRD1
gene. Successful treatment of aggression and agitation with dopaminergic blockers provides additional support for involvement of the dopaminergic system in the disruptive behavior of patients with AD.36,42
Overall, it is also conceivable that the neurobiological changes relating to disruptive behavior may involve disturbed balance in more than 1 neurotransmitter system.
This study has limitations. The patients with AD in our study were selected from tertiary care university hospitals and specialized diagnostic and treatment centers and were well educated and extremely healthy. Also, the proportion of nonwhite patients in our sample was very small (5%). Thus, they constitute a nonrandom sample of those affected by AD, and our results have limited external validity because they might not be generalizable to population-based studies of patients with AD who are of other ethnicities or other educational and comorbidity strata. Although we used survival analyses, which take advantage of variable follow-up times, a longer average duration of follow-up with enrollment of patients at even earlier stages of the disease might have provided more complete conclusions. The DBSs were assessed as present or absent. Although the severity of these symptoms is to some extent accounted for in our models by considering medications used to treat disruptive behavior (ie, the need to treat reflects symptoms’ severity according to clinical judgment), we cannot fully investigate the effects of frequency and intensity of DBSs. Medication use was coded in a dichotomous fashion for broad categories of agents. Although we used a time-dependent approach for the medication covariate, we cannot completely take into account the potential effect of different pharmacological substances, different doses, or alterations occurring in intervals shorter than 6 months. Finally, the absence of pathological correlates of DBSs may partially stem from the qualitative pathological measures we have available and from the limited power of the autopsy sample.
Confidence in our findings is strengthened by several factors. This is, to our knowledge, one of the largest studies of its kind examining the issue of disruptive behavior in AD, supplying enough power for detection and more precise calculation of effects of interest and ability to control potential confounders. Inclusion of population from 2 European centers improves the generalizability of the findings. Clinical diagnosis and follow-up were performed by physicians with specific expertise in dementia and were based on the uniform application of widely accepted criteria via consensus diagnostic conference procedures. The clinical diagnosis of AD has been confirmed in a high proportion of those who underwent postmortem evaluation (93%).23,25
The patients were followed up prospectively, which eliminates the potential biases inherent in deriving information from retrospective medical chart reviews. Evaluations were performed semiannually, which provides multiple assessments of DBSs and therefore permits more accurate coefficient calculations. They were also considered in a time-dependent fashion. Our cohort had a very high rate of follow-up participation with very few missing data. Clinical signs of interest were ascertained and coded in a standardized fashion at each visit. Most previous reports studied more impaired patients with AD, capturing the part of the disease course corresponding to more advanced stages. Patients with AD were included from relatively early stages so that the cohort captures most of the range of progression over time. Finally, we took medication administration into account in a time-dependent manner, which provides higher confidence that the occurrence of outcomes of interest in the present study is strictly related to the presence of DBSs rather than treatment for them.
Prognosis is a standard part of a medical evaluation, and knowledge of prognostic indicators is important information to practitioners, patients, and families. These data provide a basis for expanding our understanding of disruptive behavior as a predictor in the course of AD. The underlying pathophysiological substrate of the associations between such neuropsychiatric features and clinical outcomes remains to be explored.